Type 2 diabetes mellitus(T2DM)is a lifelong condition and a threat to human health.Thorough understanding of its pathogenesis is acutely needed in order to devise innovative,preventative,and potentially curative pharm...Type 2 diabetes mellitus(T2DM)is a lifelong condition and a threat to human health.Thorough understanding of its pathogenesis is acutely needed in order to devise innovative,preventative,and potentially curative pharmacological interventions.MicroRNAs(miRNA),are small,non-coding,one-stranded RNA molecules,that can target and silence around 60%of all human genes through translational repression.MiR-155 is an ancient,evolutionarily well-conserved miRNA,with distinct expression profiles and multifunctionality,and a target repertoire of over 241 genes involved in numerous physiological and pathological processes including hematopoietic lineage differentiation,immunity,inflammation,viral infections,cancer,cardiovascular conditions,and particularly diabetes mellitus.MiR-155 Levels are progressively reduced in aging,obesity,sarcopenia,and T2DM.Thus,the loss of coordinated repression of multiple miR-155 targets acting as negative regulators,such as C/EBPβ,HDAC4,and SOCS1 impacts insulin signaling,deteriorating glucose homeostasis,and causing insulin resistance(IR).Moreover,deranged regulation of the renin angiotensin aldosterone system(RAAS)through loss of Angiotensin II Type 1 receptor downregulation,and negated repression of ETS-1,results in unopposed detrimental Angiotensin II effects,further promoting IR.Finally,loss of BACH1 and SOCS1 repression abolishes cytoprotective,anti-oxidant,anti-apoptotic,and anti-inflam matory cellular pathways,and promotesβ-cell loss.In contrast to RAAS inhibitor treatments that further decrease already reduced miR-155 Levels,strategies to increase an ailing miR-155 production in T2DM,e.g.,the use of metformin,mineralocorticoid receptor blockers(spironolactone,eplerenone,finerenone),and verapamil,alone or in various combinations,represent current treatment options.In the future,direct tissue delivery of miRNA analogs is likely.展开更多
AIM: To investigate the effect of angiotensin II type 1 receptor blocker (ARB) and angiotensin converting enzyme inhibitor (ACEI) on intraocular growth factors and their receptors in streptozotocin-induced diabet...AIM: To investigate the effect of angiotensin II type 1 receptor blocker (ARB) and angiotensin converting enzyme inhibitor (ACEI) on intraocular growth factors and their receptors in streptozotocin-induced diabetic rats. METHODS: Forty Sprague-Dawley rats were divided into 4 groups: control, diabetes mellitus (DM), candesartan- treated DM, and enalapril-treated DM (each group, n---10). After the induction of DM by streptozotocin, candesartan [ARB, 5 mg/(kg · d)] and enalapril [ACEI, 10 mg/(kg · d)] were administered to rats orally for 4Wko Vascular endothelial growth factor (VEGF) and angiotensin II (Ang II) concentrations in the vitreous were measured using enzyme-linked immunosorbent assays, and VEGF receptor 2 and angiotensin II type 1 receptor (ATIR) levels were assessed at week 4 by Western blotting. RESULTS: Vitreous Ang II levels were significantly higher in the DM group and candesartan-treated DM group than in the control (P=0.04 and 0.005, respectively). Vitreous ATIR increased significantly in DM compared to the other three groups (P〈0.007). Candesartan-treated DM rats showed higher vitreal ATIR concentration than the enalapril-treated DM group and control (P〈0.001 and P=0.005, respectively). No difference in vitreous Ang II and ATIR concentration was found between the enalapril- treated DM group and control. VEGF and its receptor were below the minimum detection limit in all 4 groups. CONCLUSION: Increased Ang II and ATIR in the hyperglycemic state indicate activated the intraocular renin-angiotensin system, which is inhibited more effectively by systemic ACEI than systemic ARB.展开更多
AIM: To investigate the roles of nuclear factor(NF)-κB and angiotensin Ⅱ receptor type 1(AT1R) in the pathogenesis of non-alcoholic fatty liver disease(NAFLD).METHODS: Forty-two healthy adult male SpragueDawley rats...AIM: To investigate the roles of nuclear factor(NF)-κB and angiotensin Ⅱ receptor type 1(AT1R) in the pathogenesis of non-alcoholic fatty liver disease(NAFLD).METHODS: Forty-two healthy adult male SpragueDawley rats were randomly divided into three groups:the control group(normal diet), the model group,and the intervention group(10 wk of a high-fat diet feeding, followed by an intraperitoneal injection of PDTC); 6 rats in each group were sacrificed at 6, 10,and 14 wk. After sacrifice, liver tissue was taken,paraffin sections of liver tissue specimens were prepared, hematoxylin and eosin(HE) staining was performed, and pathological changes in liver tissue(i.e., liver fibrosis) were observed by light microscopy.NF-κB expression in liver tissue was detected by immunohistochemistry, and the expression of AT1 R in the liver tissue was detected by reverse transcriptionpolymerase chain reaction(RT-PCR). The data are expressed as mean ± SD. A two-sample t test was used to compare the control group and the model group at different time points, paired t tests were used to compare the differences between the intervention group and the model group, and analysis of variance was used to compare the model group with the control group. Homogeneity of variance was analyzed with single factor analysis of variance. H variance analysis was used to compare the variance. P < 0.05 wasconsidered statistically significant.RESULTS: The NAFLD model was successful after 6wk and 10 wk. Liver fibrosis was found in four rats in the model group, but in only one rat in the intervention group at 14 wk. Liver steatosis, inflammation, and fibrosis were gradually increased throughout the model. In the intervention group, the body mass,rat liver index, serum lipid, and transaminase levels were not increased compared to the model group.In the model group, the degree of liver steatosis was increased at 6, 10, and 14 wk, and was significantly higher than in the control group(P < 0.01). In the model group, different degrees of liver cell necrosis were visible and small leaves, punctated inflammation,focal necrosis, and obvious ballooning degeneration were observed. Partial necrosis and confluent necrosis were observed. In the model group, liver inflammatory activity scores at 6, 10, and 14 wk were higher than in the control group(P < 0.01). Active inflammation in liver tissue in the intervention group was lower than in the model group(P < 0.05). HE staining showed liver fibrosis only at 14 wk in 4/6 rats in the model group and in 1/6 rats in the intervention group. NF-κB positive cells were stained yellow or ensemble yellow,and NF-κB was localized in the cytoplasm and/or nucleus. The model group showed NF-κB activation at6, 10, and 14 wk in liver cells; at the same time points,there were statistically significant differences in the control group(P < 0.01). Over time, NF-κB expression increased; this was statistically lower(P < 0.05) at14 weeks in the intervention group compared to the model group, but significantly increased(P < 0.05)compared with the control group; RT-PCR showed that AT1 R mRNA expression increased gradually in the model group; at 14 wk, the expression was significantly different compared with expression at 10 weeks as well as at 6 weeks(P < 0.05). In the model group, AT1 R mRNA expression was significantly higher than at the same time point in the control group(P <0.01).CONCLUSION: With increasing severity of NAFLD,NF-κB activity is enhanced, and the inhibition of NF-κB activity may reduce AT1 R mRNA expression in NAFLD.展开更多
Using the latest reported homologous Chemokine receptors (PDB ID:3ODU,3OE0 and 3OE6) as templates,twenty models of angiotensin II (Ang II) type 1 (AT1) receptor (known as p30556) were generated by multiple templates h...Using the latest reported homologous Chemokine receptors (PDB ID:3ODU,3OE0 and 3OE6) as templates,twenty models of angiotensin II (Ang II) type 1 (AT1) receptor (known as p30556) were generated by multiple templates homology modeling.According to the results of the initial validation of these twenty models,the model 0020 was finally chosen as the best one for further studies.Then,a 2 ns molecular dynamic (MD) simulation for model 0020 was conducted in normal saline (0.9%,w/V) under periodical boundary conditions,which was followed by docking studies of model 0020 with several existing AT1 receptor blockers (ARBs).The docking results reveal that model 0020 possesses good affinities with these docked ARBs which are in accordance with both the IC50 inhibitor values and their curative effects.The results also show more potent interactions between the model 0020 and its ARBs than those of ever reported results,such as hydrogen bonds,hydrophobic interactions,and especially cation-π interactions and π-π interactions which have never been reported before.This may reveal that the structure of the model 0020 is quite close to its real crystal structure and the model 0020 may have the potential to be used for structure based drug design.展开更多
There is a pathophysiological correlation between arterial hypertension and diabetes mellitus, established since the pre-diabetic state in the entity known as insulin resistance. It is known that high concentrations o...There is a pathophysiological correlation between arterial hypertension and diabetes mellitus, established since the pre-diabetic state in the entity known as insulin resistance. It is known that high concentrations of angiotensin-Ⅱ enable chronic activation of the AT1 receptor, promoting sustained vasoconstriction and the consequent development of high blood pressure. Furthermore, the chronic activation of the AT1 receptor has been associated with the development of insulin resistance. From a molecular outlook, the AT1 receptor signaling pathway can activate the JNK kinase. Once activated, this kinase can block the insulin signaling pathway, favoring the resistance to this hormone. In accordance with the previously mentioned mechanisms, the negative regulation of the AT1receptor could have beneficial effects in treating metabolic syndrome and type 2diabetes mellitus. This review explains the clinical correlation of the metabolic response that diabetic patients present when receiving negatively regulatory drugs of the AT1 receptor.展开更多
Aldosterone mediates many of the physiological and pathophysiological/cardio-toxic effects of angiotensin II(Ang II). Its synthesis and secretion from the zona glomerulosa cells of the adrenal cortex, elevated in chro...Aldosterone mediates many of the physiological and pathophysiological/cardio-toxic effects of angiotensin II(Ang II). Its synthesis and secretion from the zona glomerulosa cells of the adrenal cortex, elevated in chronic heart failure(HF), is induced by Ang II type 1 receptors(AT1Rs). The AT1R is a G protein-coupled receptor, mainly coupling to Gq/11 proteins. However, it can also signal through β-arrestin-1(βarr1) or-2(βarr2), both of which mediate G protein-independent signaling. Over the past decade, a second, Gq/11 proteinindependent but βarr1-dependent signaling pathway emanating from the adrenocortical AT1R and leading to aldosterone production has become appreciated. Thus, it became apparent that AT1R antagonists that block both pathways equally well are warranted for fully effective aldosterone suppression in HF. This spurred the comparison of all of the currently marketed angiotensin receptor blockers(ARBs, AT1R antagonists or sartans) at blocking activation of the two signaling modes(G protein-, and βarr1-dependent) at the Ang IIactivated AT1R and hence, at suppression of aldosterone in vitro and in vivo. Although all agents are very potent inhibitors of G protein activation at the AT1R, candesartan and valsartan were uncovered to be the most potent ARBs at blocking βarr activation by Ang II and at suppressing aldosterone in vitro and in vivo in post-myocardial infarction HF animals. In contrast, irbesartan and losartan are virtually G protein-"biased" blockers at the human AT1R, with very low efficacy for βarr inhibition and aldosterone suppression. Therefore, candesartan and valsartan(and other, structurally similar compounds) may be the most preferred ARB agents for HF pharmacotherapy, as well as for treatment of other conditions characterized by elevated aldosterone.展开更多
Cerebral ischemia-reperfusion(I/R)injury is a crucial factor that impacts the prognosis of recanalization therapy for acute ischemic stroke(AIS).It has been found that the brain renin-angiotensin system,especially the...Cerebral ischemia-reperfusion(I/R)injury is a crucial factor that impacts the prognosis of recanalization therapy for acute ischemic stroke(AIS).It has been found that the brain renin-angiotensin system,especially the angiotensinⅡtype 1 receptor(AT1R)pathway,plays a significant role in cerebral I/R injury.This pathway is involved in processes such as oxidative stress,neuroinflammation,apoptosis,and it affects cerebrovascular autoregulation and the maintenance of blood-brain barrier.AT1R blocker(ARB),widely used as an antihypertensive agent,has demonstrated stroke prevention capabilities in numerous prospective studies,independent of its antihypertensive characteristics.Studies focusing on neurological diseases like Alzheimer's disease,Parkinson's disease,and cognitive impairment have confirmed that ARBs exhibit neuroprotective effects and aid in improving neurological functions.Preclinical studies have shown that ARBs can reduce infarct volume and brain edema,inhibit multiple signaling pathways associated with I/R injury,restore energy levels in damaged brain regions,and rescue the penumbra by promoting neovascularization in cerebral I/R models.These findings suggest that ARBs have potential to become a novel category of neuroprotecting agents for clinical treatment of Als.Therefore,this review primarily provides a theoretical foundation and practical evidence for the future clinical utilization of ARBs as neuroprotective agents following reperfusion therapy for Als.It outlines the role of cerebral I/R injury through the AT1R pathway and highlights the research progressmadeonARBs in I/Rmodels.展开更多
AIM To investigate effect of losartan,an AT1receptor antagonist,on hepatic fibrosis induced byCCl<sub>;</sub>and to determine whether or not AT1receptors are expressed on hepatic stellate cells,METHODS AND...AIM To investigate effect of losartan,an AT1receptor antagonist,on hepatic fibrosis induced byCCl<sub>;</sub>and to determine whether or not AT1receptors are expressed on hepatic stellate cells,METHODS AND RESULTS Fifty male Sprague-Dawley rats,weighing(180±20)g,wererandomized into five groups(control group,modelgroup,and three losartan treated groups),inwhich all rats were given the subcutaneousinjection of 40% CCl<sub>4</sub>(every 3 days for 6 weeks)except for rats of control group.Rats of losartan-treated groups were treated with losartan(20 mg/kg,10 mg/kg,5 mg/kg,daily gavage),After 6weeks liver tissue and serum samples of all ratswere examined.Serum hyaluronic acid(HA),procollagen typeⅢ(PCⅢ)were detected byradioimmunoassays,van Giesion collagen stainingwas used to evaluate the extracellular matrix of ratswith liver fibrosis.The expression of AT1receptors,transforming growth factor-beta(TGF-β),and alpha-smooth muscle actin(a-SMA)inliver tissue were determined byimmunohistochemical techniques.Compared withmodel group,serum ALT and AST of losartan-treated groups were significantly reduced(t=4.20,P【0.01 and t=4.57,P【0.01).Serum HAand PCⅢalso had significant differences(t=3.53,P【0.01 and t=2.20,P【0.05).Thedegree of fibrosis was improved by losartan and correlated with the expressions of AT1 receptors,TGF-β,and α-SMA in liver tissue.CONCLUSION AT1 receptor antagonist,losartan,could limit the progression of the hepatic fibrosisinduced by CCl<sub>4</sub>.The mechanism may be related tothe decrease in the expression of AT1 receptorsand TGF-β,ameliorating the injury of hepatocytes;activation of local renin-angiotensin system mightrelate to hepatic fibrosis;and during progressionof fibrosis,activated hepatic stellate cells mightexpress AT1 receptors.展开更多
Angiotensin-(1 - 7) [Ang-(1 - 7)] is an endogenous heptapeptide hormone of the renin-angiotensin system that has antiproliferative properties. The aim of this work was to evaluate the anti-proliferative and pro-apopto...Angiotensin-(1 - 7) [Ang-(1 - 7)] is an endogenous heptapeptide hormone of the renin-angiotensin system that has antiproliferative properties. The aim of this work was to evaluate the anti-proliferative and pro-apoptotic properties of Ang-(1 - 7) and of Ang-(1 - 7)-substituents 9-fluorenylmethyloxycarbonyl (Fmoc) e Ang II-derivatives containing the TOAC (2,2,6,6-tetramethylpiperidine-N-oxyl-4-amino-4-carboxylic acid) in normal (MCF10A) and in tumoral (MCF7) epithelial mammary cell lines. Both cell lines received an hCG and angiotensin peptides 24-hour treatment, in combination or alone followed by cell viability, apoptosis and cell cycle assays performed by flow cytometer (GUAVA). After hCG, Ang-(1 - 7), hCG + Ang-(1 - 7) and hCG + Ang-(1 - 7)-Fmoc treatments, MCF7 displayed cell viability decrease and mid-apoptosis increase. We also observed cell viability decrease in MCF10A after Ang-(1 - 7), Ang-(1 - 7) Fmoc and hCG + AngII Toac treatments. These cells had an increase in late apoptosis and necrosis after AngII Toac, hCG + Ang-(1 - 7) and hCG + Ang-(1 - 7)-Fmoc treatments. Regarding the cell cycle analysis, we did not observed any changes in cell cycle phases. In summary, cell viability was decreased and apoptosis (initial, mid and late) was increased after hCG and/or Ang-(1 - 7) peptides treatments. These results point out hCG and Ang-(1 - 7) as effective compounds to inhibit cell proliferation, since they decrease cell viability and increase apoptosis in both normal and in tumoral breast cells, being the effect more pronounced in the tumoral cell line. Our results support the idea of investigating more closely the putative use of these compounds as novel therapeutic agents for breast cancer.展开更多
Background: Breast cancer is the most common type of cancer among women. Diagnosed and treated timely, patients may have good prognostics. In Brazil, in 2012, the estimate of new cases was 52,680 and the number of reg...Background: Breast cancer is the most common type of cancer among women. Diagnosed and treated timely, patients may have good prognostics. In Brazil, in 2012, the estimate of new cases was 52,680 and the number of registered deaths in 2012 was 12,852. The Renin-Angiotensin System (RAS) is known for its role in arterial hypertension and in other cardiovascular diseases. Angiotensin-Converting Enzyme 2 (ACE2) is the key to Ang-(1-7) formation, and counterbalances the ACE1/AngII/AGTR1 axis actions. RAS components have complex interactions with different tissues and their actions are not restricted to the cardiovascular system. Recently, the RAS has been associated with different types of cancers and in particular with gynecological cancers. Objectives: Our aim is to investigate possible associations between allelic distribution of two genetic polymorphisms in the AGTR2 receptor with ACEs 1 and 2 plasma levels among women with breast cancer. Patients and Methods: Patients with breast cancer were genotyped for two polymorphisms of the AGTR2 (T1247G and A5235G). Genotyping assays (TaqMan) were performed with genomic DNA extracted from blood cells. ACEs plasma level measurements were conducted in women from the breast-cancer group (N = 53). ACEs were measured in the plasma of these patients using ELISA kits. Results: SNPs genotype distribution is correlated with ACEs plasma levels. ACEs plasma levels are also correlated with clinical variables and ACE2 high levels are associated with better prognostics. Conclusions: Changes in circulating levels of ECA1/AngII ECA2/ Ang-(1-7) determine the magnitude of the inflammatory response that an individual can trigger and the variation in ACE 1 and 2 plasma level measurements in the blood of breast cancer patients suggests an association with the process of mammary carcinogenesis. Thus, the RAS may be associated with the process of mammary carcinogenesis by both genotypic variations of RAS components and by circulating levels of ACEs.展开更多
Background Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II type 1 receptor blockers (ARB) can inhibit tumor growth by inhibition of angiogenesis. This study was designed to study the anticancer ...Background Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II type 1 receptor blockers (ARB) can inhibit tumor growth by inhibition of angiogenesis. This study was designed to study the anticancer effects of ACEI and ARB on tumor growth and lymphangiogenesis in an implanted gastric cancer mouse model. Methods A model of gastric cancer was established by subcutaneously inoculating human gastric cancer cell line SGC-7901 into 60 nude mice. One week later, all mice were randomly divided into 5 groups. A control group received physiologic saline once daily for 21 days. Mice in the 4 treatment groups received one of the following agents by gavage once daily for 21 days: perindopril, 2 mg/kg; captopril, 5 mg/kg; Iosartan, 50 mg/kg; or valsartan, 40 mg/kg. Twenty-one days after treatment, all the mice were sacrificed and the tumors were removed. Tumor sections were processed, and immunohistochemical methods were used to observe the expressions of vascular endothelial growth factor C (VEGF-C), matrix metalloproteinase 7 (MMP-7), and lymphatic microvessel density (LMVD). Results Tumor volume was significantly inhibited in all ACEI and ARB groups, compared with the control group (all P 〈0,01). LMVD in the ACEI and ARB groups was also significantly lower than that of the control group (all P 〈0.01). In the ACEI groups, the expressions of VEGF-C and MMP-7 were both significantly decreased, compared with the control group (all P 〈0.05). In the ARB groups, expression of VEGF-C was significantly decreased compared with the control group (all P 〈0.05). However, no significant difference was found in the expression of MMP-7 between ARB groups and the control group. Conclusion In a mouse model, ACEI and ARB might inhibit gastric cancer tumor growth by suppressing lymphangiogenesis.展开更多
Portal hypertension is responsible for the bulk of the morbidity and mortality in patients with cirrhosis.Drug therapy to reduce portal pressure involves targeting two vascular beds.The first approach is to reduce int...Portal hypertension is responsible for the bulk of the morbidity and mortality in patients with cirrhosis.Drug therapy to reduce portal pressure involves targeting two vascular beds.The first approach is to reduce intra hepatic vascular tone induced by the activity of powerful vasocontrictors such as angiotensin Ⅱ,endothelin-1 and the sympathetic system and mediated via contraction of perisinusoidal myofibroblasts and pervascular smooth muscle cells.The second approach is to reduce mesenteric and portal blood flow.Non-selective b-blockers are widely used and have been shown to prolong patient survival and reduce oesophageal variceal bleeding in advanced cirrhosis.However many patients are unable to tolerate these drugs and they are ineffective in a significant proportion of patients.Unfortunately there are no other drug therapies that have proven efficacy in the treatment of portal hypertension and prevention of variceal bleeding.This review briefly outlines current therapeutic approaches to themanagement of portal hypertension,and the evidence supporting the role of the renin angiotensin system(RAS) and the use of RAS blockers in this condition.It will also outline recent advances in RAS research that could lead to the development of new treatments focusing in particular on the recently discovered "alternate axis" of the RAS.展开更多
In adipose tissue of rats on long-term high fat diet, the inflammatory changes the roles of angiotensin receptor blocker (ARB) in pimelitis and insulin resistance (IR) were observed. LR rat model was established b...In adipose tissue of rats on long-term high fat diet, the inflammatory changes the roles of angiotensin receptor blocker (ARB) in pimelitis and insulin resistance (IR) were observed. LR rat model was established by feeding high calorie and high fat diet. The change in insulin sensitivity was detected by euglycemic-hyperinsulinemic clamp technique 8 weeks after intervention by valsartan. The expression levels of CD68 and MCP-1 mRNA and proteins in adipose tissue were examined by RT-PCR and immunohistochemistry respectively. The parameters of blood glucose, insulin and blood lipid were analyzed. The results showed that in high fat diet group intra-abdominal obesity developed the content of visceral fat and the number of inflammatory cells in local adipose tissue were significantly increased (P〈0.01), the levels of serum triglyceride, free fatty acids and fasting serum insulin were markedly increased, the insulin sensitivity was significantly lowered (P〈0.01), and the expression of CD68 and MCP-1 was significantly increased as compared with control group (P〈0.01). In ARB interventional group, the content of visceral fat, the number of inflammatory cells and the ex- pression of CD68 and MCP-1 in local adipose tissue were significantly reduced (all P〈0.01), but the insulin sensitivity was significantly enhanced (P〈0.01) as compared with high fat diet group. There were pimelitis and IR in rats with obesity induced by long-term high calorie and high fat diet. The ARB can significantly inhibit the infiltration of macrophages and the expression of MCP-1 in adipose tissue, thereby attenuating the inflammation and improving LR in rats.展开更多
BACKGROUND Obesity has been associated with hepatic overexpression of the renin-angiotensin system(RAS).AIM To evaluate the action of two angiotensin II(ANGII) receptor blockers(losartan or telmisartan) on the modulat...BACKGROUND Obesity has been associated with hepatic overexpression of the renin-angiotensin system(RAS).AIM To evaluate the action of two angiotensin II(ANGII) receptor blockers(losartan or telmisartan) on the modulation of local hepatic RAS and the resulting metabolic effects in a diet-induced obesity murine model.METHODS Twenty C57 BL/6 mice were randomly divided into two nutritional groups for 10 wk: control group(C, n = 5, 10% of energy as fat) or high-fat group(HF, n = 15,50% of energy as fat). After treatment started, the HF group was randomly divided into three groups: untreated HF group(n = 5), HF treated with losartan(HFL, n = 5) and HF treated with telmisartan(HFT, n = 5). The treatments lasted for 5 wk, and the dose was 10 mg/kg body mass.RESULTS HF diet induced body mass gain(+28%, P < 0.0001), insulin resistance(+69%, P =0.0079), high hepatic triacylglycerol(+127%, P = 0.0004), and overexpression of intrahepatic angiotensin-converting enzyme(ACE) 1/ANGII type 1 receptor(AT1 r)(+569.02% and +141.40%, respectively, P < 0.0001). The HFL and HFT groups showed higher ACE2/rMAS gene expression compared to the HF group(ACE2: +465.57%, P = 0.0002 for HFL and +345.17%, P = 0.0049 for HFT; rMAS:+711.39%, P < 0.0001 for HFL and +539.75%, P < 0.0001 for HFT), followed by reduced insulin/glucose ratio(-30% for HFL and-33% for HFT, P = 0.0181),hepatic triacylglycerol levels(-28%, P = 0.0381 for HFL; and-45%, P = 0.0010 for HFT, and Plin2 expression.CONCLUSION Modulation of the intrahepatic RAS, with favored involvement of the ACE2/rMAS axis over the ACE1/AT1 r axis after losartan or telmisartan treatments, caused hepatic and metabolic beneficial effects as demonstrated by reduced hepatic triacylglycerol levels coupled with reduced PLIN 2 expression and improved glycemic control.展开更多
文摘Type 2 diabetes mellitus(T2DM)is a lifelong condition and a threat to human health.Thorough understanding of its pathogenesis is acutely needed in order to devise innovative,preventative,and potentially curative pharmacological interventions.MicroRNAs(miRNA),are small,non-coding,one-stranded RNA molecules,that can target and silence around 60%of all human genes through translational repression.MiR-155 is an ancient,evolutionarily well-conserved miRNA,with distinct expression profiles and multifunctionality,and a target repertoire of over 241 genes involved in numerous physiological and pathological processes including hematopoietic lineage differentiation,immunity,inflammation,viral infections,cancer,cardiovascular conditions,and particularly diabetes mellitus.MiR-155 Levels are progressively reduced in aging,obesity,sarcopenia,and T2DM.Thus,the loss of coordinated repression of multiple miR-155 targets acting as negative regulators,such as C/EBPβ,HDAC4,and SOCS1 impacts insulin signaling,deteriorating glucose homeostasis,and causing insulin resistance(IR).Moreover,deranged regulation of the renin angiotensin aldosterone system(RAAS)through loss of Angiotensin II Type 1 receptor downregulation,and negated repression of ETS-1,results in unopposed detrimental Angiotensin II effects,further promoting IR.Finally,loss of BACH1 and SOCS1 repression abolishes cytoprotective,anti-oxidant,anti-apoptotic,and anti-inflam matory cellular pathways,and promotesβ-cell loss.In contrast to RAAS inhibitor treatments that further decrease already reduced miR-155 Levels,strategies to increase an ailing miR-155 production in T2DM,e.g.,the use of metformin,mineralocorticoid receptor blockers(spironolactone,eplerenone,finerenone),and verapamil,alone or in various combinations,represent current treatment options.In the future,direct tissue delivery of miRNA analogs is likely.
基金Supported by Biomedical Research Institute Grant(PNU-2013-0373),Pusan National University Hospital
文摘AIM: To investigate the effect of angiotensin II type 1 receptor blocker (ARB) and angiotensin converting enzyme inhibitor (ACEI) on intraocular growth factors and their receptors in streptozotocin-induced diabetic rats. METHODS: Forty Sprague-Dawley rats were divided into 4 groups: control, diabetes mellitus (DM), candesartan- treated DM, and enalapril-treated DM (each group, n---10). After the induction of DM by streptozotocin, candesartan [ARB, 5 mg/(kg · d)] and enalapril [ACEI, 10 mg/(kg · d)] were administered to rats orally for 4Wko Vascular endothelial growth factor (VEGF) and angiotensin II (Ang II) concentrations in the vitreous were measured using enzyme-linked immunosorbent assays, and VEGF receptor 2 and angiotensin II type 1 receptor (ATIR) levels were assessed at week 4 by Western blotting. RESULTS: Vitreous Ang II levels were significantly higher in the DM group and candesartan-treated DM group than in the control (P=0.04 and 0.005, respectively). Vitreous ATIR increased significantly in DM compared to the other three groups (P〈0.007). Candesartan-treated DM rats showed higher vitreal ATIR concentration than the enalapril-treated DM group and control (P〈0.001 and P=0.005, respectively). No difference in vitreous Ang II and ATIR concentration was found between the enalapril- treated DM group and control. VEGF and its receptor were below the minimum detection limit in all 4 groups. CONCLUSION: Increased Ang II and ATIR in the hyperglycemic state indicate activated the intraocular renin-angiotensin system, which is inhibited more effectively by systemic ACEI than systemic ARB.
基金Supported by grants from the Science and Technology Department of Sichuan Province,No.2011SZ0094
文摘AIM: To investigate the roles of nuclear factor(NF)-κB and angiotensin Ⅱ receptor type 1(AT1R) in the pathogenesis of non-alcoholic fatty liver disease(NAFLD).METHODS: Forty-two healthy adult male SpragueDawley rats were randomly divided into three groups:the control group(normal diet), the model group,and the intervention group(10 wk of a high-fat diet feeding, followed by an intraperitoneal injection of PDTC); 6 rats in each group were sacrificed at 6, 10,and 14 wk. After sacrifice, liver tissue was taken,paraffin sections of liver tissue specimens were prepared, hematoxylin and eosin(HE) staining was performed, and pathological changes in liver tissue(i.e., liver fibrosis) were observed by light microscopy.NF-κB expression in liver tissue was detected by immunohistochemistry, and the expression of AT1 R in the liver tissue was detected by reverse transcriptionpolymerase chain reaction(RT-PCR). The data are expressed as mean ± SD. A two-sample t test was used to compare the control group and the model group at different time points, paired t tests were used to compare the differences between the intervention group and the model group, and analysis of variance was used to compare the model group with the control group. Homogeneity of variance was analyzed with single factor analysis of variance. H variance analysis was used to compare the variance. P < 0.05 wasconsidered statistically significant.RESULTS: The NAFLD model was successful after 6wk and 10 wk. Liver fibrosis was found in four rats in the model group, but in only one rat in the intervention group at 14 wk. Liver steatosis, inflammation, and fibrosis were gradually increased throughout the model. In the intervention group, the body mass,rat liver index, serum lipid, and transaminase levels were not increased compared to the model group.In the model group, the degree of liver steatosis was increased at 6, 10, and 14 wk, and was significantly higher than in the control group(P < 0.01). In the model group, different degrees of liver cell necrosis were visible and small leaves, punctated inflammation,focal necrosis, and obvious ballooning degeneration were observed. Partial necrosis and confluent necrosis were observed. In the model group, liver inflammatory activity scores at 6, 10, and 14 wk were higher than in the control group(P < 0.01). Active inflammation in liver tissue in the intervention group was lower than in the model group(P < 0.05). HE staining showed liver fibrosis only at 14 wk in 4/6 rats in the model group and in 1/6 rats in the intervention group. NF-κB positive cells were stained yellow or ensemble yellow,and NF-κB was localized in the cytoplasm and/or nucleus. The model group showed NF-κB activation at6, 10, and 14 wk in liver cells; at the same time points,there were statistically significant differences in the control group(P < 0.01). Over time, NF-κB expression increased; this was statistically lower(P < 0.05) at14 weeks in the intervention group compared to the model group, but significantly increased(P < 0.05)compared with the control group; RT-PCR showed that AT1 R mRNA expression increased gradually in the model group; at 14 wk, the expression was significantly different compared with expression at 10 weeks as well as at 6 weeks(P < 0.05). In the model group, AT1 R mRNA expression was significantly higher than at the same time point in the control group(P <0.01).CONCLUSION: With increasing severity of NAFLD,NF-κB activity is enhanced, and the inhibition of NF-κB activity may reduce AT1 R mRNA expression in NAFLD.
基金Project(20876180)supported by the National Natural Science Foundation of China
文摘Using the latest reported homologous Chemokine receptors (PDB ID:3ODU,3OE0 and 3OE6) as templates,twenty models of angiotensin II (Ang II) type 1 (AT1) receptor (known as p30556) were generated by multiple templates homology modeling.According to the results of the initial validation of these twenty models,the model 0020 was finally chosen as the best one for further studies.Then,a 2 ns molecular dynamic (MD) simulation for model 0020 was conducted in normal saline (0.9%,w/V) under periodical boundary conditions,which was followed by docking studies of model 0020 with several existing AT1 receptor blockers (ARBs).The docking results reveal that model 0020 possesses good affinities with these docked ARBs which are in accordance with both the IC50 inhibitor values and their curative effects.The results also show more potent interactions between the model 0020 and its ARBs than those of ever reported results,such as hydrogen bonds,hydrophobic interactions,and especially cation-π interactions and π-π interactions which have never been reported before.This may reveal that the structure of the model 0020 is quite close to its real crystal structure and the model 0020 may have the potential to be used for structure based drug design.
文摘There is a pathophysiological correlation between arterial hypertension and diabetes mellitus, established since the pre-diabetic state in the entity known as insulin resistance. It is known that high concentrations of angiotensin-Ⅱ enable chronic activation of the AT1 receptor, promoting sustained vasoconstriction and the consequent development of high blood pressure. Furthermore, the chronic activation of the AT1 receptor has been associated with the development of insulin resistance. From a molecular outlook, the AT1 receptor signaling pathway can activate the JNK kinase. Once activated, this kinase can block the insulin signaling pathway, favoring the resistance to this hormone. In accordance with the previously mentioned mechanisms, the negative regulation of the AT1receptor could have beneficial effects in treating metabolic syndrome and type 2diabetes mellitus. This review explains the clinical correlation of the metabolic response that diabetic patients present when receiving negatively regulatory drugs of the AT1 receptor.
文摘Aldosterone mediates many of the physiological and pathophysiological/cardio-toxic effects of angiotensin II(Ang II). Its synthesis and secretion from the zona glomerulosa cells of the adrenal cortex, elevated in chronic heart failure(HF), is induced by Ang II type 1 receptors(AT1Rs). The AT1R is a G protein-coupled receptor, mainly coupling to Gq/11 proteins. However, it can also signal through β-arrestin-1(βarr1) or-2(βarr2), both of which mediate G protein-independent signaling. Over the past decade, a second, Gq/11 proteinindependent but βarr1-dependent signaling pathway emanating from the adrenocortical AT1R and leading to aldosterone production has become appreciated. Thus, it became apparent that AT1R antagonists that block both pathways equally well are warranted for fully effective aldosterone suppression in HF. This spurred the comparison of all of the currently marketed angiotensin receptor blockers(ARBs, AT1R antagonists or sartans) at blocking activation of the two signaling modes(G protein-, and βarr1-dependent) at the Ang IIactivated AT1R and hence, at suppression of aldosterone in vitro and in vivo. Although all agents are very potent inhibitors of G protein activation at the AT1R, candesartan and valsartan were uncovered to be the most potent ARBs at blocking βarr activation by Ang II and at suppressing aldosterone in vitro and in vivo in post-myocardial infarction HF animals. In contrast, irbesartan and losartan are virtually G protein-"biased" blockers at the human AT1R, with very low efficacy for βarr inhibition and aldosterone suppression. Therefore, candesartan and valsartan(and other, structurally similar compounds) may be the most preferred ARB agents for HF pharmacotherapy, as well as for treatment of other conditions characterized by elevated aldosterone.
基金Chongqing Science and Health Joint Medical ResearchProject,Grant/AwardNumber:2024MSXM124。
文摘Cerebral ischemia-reperfusion(I/R)injury is a crucial factor that impacts the prognosis of recanalization therapy for acute ischemic stroke(AIS).It has been found that the brain renin-angiotensin system,especially the angiotensinⅡtype 1 receptor(AT1R)pathway,plays a significant role in cerebral I/R injury.This pathway is involved in processes such as oxidative stress,neuroinflammation,apoptosis,and it affects cerebrovascular autoregulation and the maintenance of blood-brain barrier.AT1R blocker(ARB),widely used as an antihypertensive agent,has demonstrated stroke prevention capabilities in numerous prospective studies,independent of its antihypertensive characteristics.Studies focusing on neurological diseases like Alzheimer's disease,Parkinson's disease,and cognitive impairment have confirmed that ARBs exhibit neuroprotective effects and aid in improving neurological functions.Preclinical studies have shown that ARBs can reduce infarct volume and brain edema,inhibit multiple signaling pathways associated with I/R injury,restore energy levels in damaged brain regions,and rescue the penumbra by promoting neovascularization in cerebral I/R models.These findings suggest that ARBs have potential to become a novel category of neuroprotecting agents for clinical treatment of Als.Therefore,this review primarily provides a theoretical foundation and practical evidence for the future clinical utilization of ARBs as neuroprotective agents following reperfusion therapy for Als.It outlines the role of cerebral I/R injury through the AT1R pathway and highlights the research progressmadeonARBs in I/Rmodels.
文摘AIM To investigate effect of losartan,an AT1receptor antagonist,on hepatic fibrosis induced byCCl<sub>;</sub>and to determine whether or not AT1receptors are expressed on hepatic stellate cells,METHODS AND RESULTS Fifty male Sprague-Dawley rats,weighing(180±20)g,wererandomized into five groups(control group,modelgroup,and three losartan treated groups),inwhich all rats were given the subcutaneousinjection of 40% CCl<sub>4</sub>(every 3 days for 6 weeks)except for rats of control group.Rats of losartan-treated groups were treated with losartan(20 mg/kg,10 mg/kg,5 mg/kg,daily gavage),After 6weeks liver tissue and serum samples of all ratswere examined.Serum hyaluronic acid(HA),procollagen typeⅢ(PCⅢ)were detected byradioimmunoassays,van Giesion collagen stainingwas used to evaluate the extracellular matrix of ratswith liver fibrosis.The expression of AT1receptors,transforming growth factor-beta(TGF-β),and alpha-smooth muscle actin(a-SMA)inliver tissue were determined byimmunohistochemical techniques.Compared withmodel group,serum ALT and AST of losartan-treated groups were significantly reduced(t=4.20,P【0.01 and t=4.57,P【0.01).Serum HAand PCⅢalso had significant differences(t=3.53,P【0.01 and t=2.20,P【0.05).Thedegree of fibrosis was improved by losartan and correlated with the expressions of AT1 receptors,TGF-β,and α-SMA in liver tissue.CONCLUSION AT1 receptor antagonist,losartan,could limit the progression of the hepatic fibrosisinduced by CCl<sub>4</sub>.The mechanism may be related tothe decrease in the expression of AT1 receptorsand TGF-β,ameliorating the injury of hepatocytes;activation of local renin-angiotensin system mightrelate to hepatic fibrosis;and during progressionof fibrosis,activated hepatic stellate cells mightexpress AT1 receptors.
基金supported by Grants number 2007/56480-0,2008/54383-0 and 2011/10516-0 from the Sao Paulo Research Foundation(FAPESP)-Brazil.
文摘Angiotensin-(1 - 7) [Ang-(1 - 7)] is an endogenous heptapeptide hormone of the renin-angiotensin system that has antiproliferative properties. The aim of this work was to evaluate the anti-proliferative and pro-apoptotic properties of Ang-(1 - 7) and of Ang-(1 - 7)-substituents 9-fluorenylmethyloxycarbonyl (Fmoc) e Ang II-derivatives containing the TOAC (2,2,6,6-tetramethylpiperidine-N-oxyl-4-amino-4-carboxylic acid) in normal (MCF10A) and in tumoral (MCF7) epithelial mammary cell lines. Both cell lines received an hCG and angiotensin peptides 24-hour treatment, in combination or alone followed by cell viability, apoptosis and cell cycle assays performed by flow cytometer (GUAVA). After hCG, Ang-(1 - 7), hCG + Ang-(1 - 7) and hCG + Ang-(1 - 7)-Fmoc treatments, MCF7 displayed cell viability decrease and mid-apoptosis increase. We also observed cell viability decrease in MCF10A after Ang-(1 - 7), Ang-(1 - 7) Fmoc and hCG + AngII Toac treatments. These cells had an increase in late apoptosis and necrosis after AngII Toac, hCG + Ang-(1 - 7) and hCG + Ang-(1 - 7)-Fmoc treatments. Regarding the cell cycle analysis, we did not observed any changes in cell cycle phases. In summary, cell viability was decreased and apoptosis (initial, mid and late) was increased after hCG and/or Ang-(1 - 7) peptides treatments. These results point out hCG and Ang-(1 - 7) as effective compounds to inhibit cell proliferation, since they decrease cell viability and increase apoptosis in both normal and in tumoral breast cells, being the effect more pronounced in the tumoral cell line. Our results support the idea of investigating more closely the putative use of these compounds as novel therapeutic agents for breast cancer.
文摘Background: Breast cancer is the most common type of cancer among women. Diagnosed and treated timely, patients may have good prognostics. In Brazil, in 2012, the estimate of new cases was 52,680 and the number of registered deaths in 2012 was 12,852. The Renin-Angiotensin System (RAS) is known for its role in arterial hypertension and in other cardiovascular diseases. Angiotensin-Converting Enzyme 2 (ACE2) is the key to Ang-(1-7) formation, and counterbalances the ACE1/AngII/AGTR1 axis actions. RAS components have complex interactions with different tissues and their actions are not restricted to the cardiovascular system. Recently, the RAS has been associated with different types of cancers and in particular with gynecological cancers. Objectives: Our aim is to investigate possible associations between allelic distribution of two genetic polymorphisms in the AGTR2 receptor with ACEs 1 and 2 plasma levels among women with breast cancer. Patients and Methods: Patients with breast cancer were genotyped for two polymorphisms of the AGTR2 (T1247G and A5235G). Genotyping assays (TaqMan) were performed with genomic DNA extracted from blood cells. ACEs plasma level measurements were conducted in women from the breast-cancer group (N = 53). ACEs were measured in the plasma of these patients using ELISA kits. Results: SNPs genotype distribution is correlated with ACEs plasma levels. ACEs plasma levels are also correlated with clinical variables and ACE2 high levels are associated with better prognostics. Conclusions: Changes in circulating levels of ECA1/AngII ECA2/ Ang-(1-7) determine the magnitude of the inflammatory response that an individual can trigger and the variation in ACE 1 and 2 plasma level measurements in the blood of breast cancer patients suggests an association with the process of mammary carcinogenesis. Thus, the RAS may be associated with the process of mammary carcinogenesis by both genotypic variations of RAS components and by circulating levels of ACEs.
基金This study was supported by a grant from the Guangdong Province Natural Science Foundation (No. 5001766).
文摘Background Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II type 1 receptor blockers (ARB) can inhibit tumor growth by inhibition of angiogenesis. This study was designed to study the anticancer effects of ACEI and ARB on tumor growth and lymphangiogenesis in an implanted gastric cancer mouse model. Methods A model of gastric cancer was established by subcutaneously inoculating human gastric cancer cell line SGC-7901 into 60 nude mice. One week later, all mice were randomly divided into 5 groups. A control group received physiologic saline once daily for 21 days. Mice in the 4 treatment groups received one of the following agents by gavage once daily for 21 days: perindopril, 2 mg/kg; captopril, 5 mg/kg; Iosartan, 50 mg/kg; or valsartan, 40 mg/kg. Twenty-one days after treatment, all the mice were sacrificed and the tumors were removed. Tumor sections were processed, and immunohistochemical methods were used to observe the expressions of vascular endothelial growth factor C (VEGF-C), matrix metalloproteinase 7 (MMP-7), and lymphatic microvessel density (LMVD). Results Tumor volume was significantly inhibited in all ACEI and ARB groups, compared with the control group (all P 〈0,01). LMVD in the ACEI and ARB groups was also significantly lower than that of the control group (all P 〈0.01). In the ACEI groups, the expressions of VEGF-C and MMP-7 were both significantly decreased, compared with the control group (all P 〈0.05). In the ARB groups, expression of VEGF-C was significantly decreased compared with the control group (all P 〈0.05). However, no significant difference was found in the expression of MMP-7 between ARB groups and the control group. Conclusion In a mouse model, ACEI and ARB might inhibit gastric cancer tumor growth by suppressing lymphangiogenesis.
基金Supported by Grant from the National Health and Medical Research Council of Australia
文摘Portal hypertension is responsible for the bulk of the morbidity and mortality in patients with cirrhosis.Drug therapy to reduce portal pressure involves targeting two vascular beds.The first approach is to reduce intra hepatic vascular tone induced by the activity of powerful vasocontrictors such as angiotensin Ⅱ,endothelin-1 and the sympathetic system and mediated via contraction of perisinusoidal myofibroblasts and pervascular smooth muscle cells.The second approach is to reduce mesenteric and portal blood flow.Non-selective b-blockers are widely used and have been shown to prolong patient survival and reduce oesophageal variceal bleeding in advanced cirrhosis.However many patients are unable to tolerate these drugs and they are ineffective in a significant proportion of patients.Unfortunately there are no other drug therapies that have proven efficacy in the treatment of portal hypertension and prevention of variceal bleeding.This review briefly outlines current therapeutic approaches to themanagement of portal hypertension,and the evidence supporting the role of the renin angiotensin system(RAS) and the use of RAS blockers in this condition.It will also outline recent advances in RAS research that could lead to the development of new treatments focusing in particular on the recently discovered "alternate axis" of the RAS.
基金a grant from Natural Science Foundation of Hubei Province,China (No. 2005ABA185)
文摘In adipose tissue of rats on long-term high fat diet, the inflammatory changes the roles of angiotensin receptor blocker (ARB) in pimelitis and insulin resistance (IR) were observed. LR rat model was established by feeding high calorie and high fat diet. The change in insulin sensitivity was detected by euglycemic-hyperinsulinemic clamp technique 8 weeks after intervention by valsartan. The expression levels of CD68 and MCP-1 mRNA and proteins in adipose tissue were examined by RT-PCR and immunohistochemistry respectively. The parameters of blood glucose, insulin and blood lipid were analyzed. The results showed that in high fat diet group intra-abdominal obesity developed the content of visceral fat and the number of inflammatory cells in local adipose tissue were significantly increased (P〈0.01), the levels of serum triglyceride, free fatty acids and fasting serum insulin were markedly increased, the insulin sensitivity was significantly lowered (P〈0.01), and the expression of CD68 and MCP-1 was significantly increased as compared with control group (P〈0.01). In ARB interventional group, the content of visceral fat, the number of inflammatory cells and the ex- pression of CD68 and MCP-1 in local adipose tissue were significantly reduced (all P〈0.01), but the insulin sensitivity was significantly enhanced (P〈0.01) as compared with high fat diet group. There were pimelitis and IR in rats with obesity induced by long-term high calorie and high fat diet. The ARB can significantly inhibit the infiltration of macrophages and the expression of MCP-1 in adipose tissue, thereby attenuating the inflammation and improving LR in rats.
基金Fundacao Carlos Chagas Filho de Apoio aPesquisa do Estado do Rio de Janeiro,No.E-26/202.888/2015 for V.S-M
文摘BACKGROUND Obesity has been associated with hepatic overexpression of the renin-angiotensin system(RAS).AIM To evaluate the action of two angiotensin II(ANGII) receptor blockers(losartan or telmisartan) on the modulation of local hepatic RAS and the resulting metabolic effects in a diet-induced obesity murine model.METHODS Twenty C57 BL/6 mice were randomly divided into two nutritional groups for 10 wk: control group(C, n = 5, 10% of energy as fat) or high-fat group(HF, n = 15,50% of energy as fat). After treatment started, the HF group was randomly divided into three groups: untreated HF group(n = 5), HF treated with losartan(HFL, n = 5) and HF treated with telmisartan(HFT, n = 5). The treatments lasted for 5 wk, and the dose was 10 mg/kg body mass.RESULTS HF diet induced body mass gain(+28%, P < 0.0001), insulin resistance(+69%, P =0.0079), high hepatic triacylglycerol(+127%, P = 0.0004), and overexpression of intrahepatic angiotensin-converting enzyme(ACE) 1/ANGII type 1 receptor(AT1 r)(+569.02% and +141.40%, respectively, P < 0.0001). The HFL and HFT groups showed higher ACE2/rMAS gene expression compared to the HF group(ACE2: +465.57%, P = 0.0002 for HFL and +345.17%, P = 0.0049 for HFT; rMAS:+711.39%, P < 0.0001 for HFL and +539.75%, P < 0.0001 for HFT), followed by reduced insulin/glucose ratio(-30% for HFL and-33% for HFT, P = 0.0181),hepatic triacylglycerol levels(-28%, P = 0.0381 for HFL; and-45%, P = 0.0010 for HFT, and Plin2 expression.CONCLUSION Modulation of the intrahepatic RAS, with favored involvement of the ACE2/rMAS axis over the ACE1/AT1 r axis after losartan or telmisartan treatments, caused hepatic and metabolic beneficial effects as demonstrated by reduced hepatic triacylglycerol levels coupled with reduced PLIN 2 expression and improved glycemic control.