Role of angiotensin receptor-neprilysin inhibitor in diabetic complications

Diabetes mellitus is a prevalent disorder with multi-system manifestations,causing a significant burden in terms of disability and deaths globally.Angio-tensin receptor-neprilysin inhibitor(ARNI)belongs to a class of medications for treating heart failure,with the benefits of reducing hospitalization rates and mortality.This review mainly focuses on the clinical and basic investigations related to ARNI and diabetic complications,discussing possible physiological and molecular mechanisms,with insights for future applications.

The Role for AVE0991 (MAS-Receptor Angiotensin II (1-7) Agonist) in Reducing Cisplatin-Induced Acute Kidney Injury on C57BL/6 Mice

Acute Kidney Injury (AKI) is a condition that causes nephrotoxicity in kidney tissues due to cisplatin-induced cancer treatments. Hence, it is proposed in this review that AVE0991 (a MAS-receptor Angiotensin II (1-7) agonist) may reduce cisplatin-induced acute kidney injury by promoting nitric oxide production.

Influence of Angiotensin II on α1-Adrenergic Receptors Function in Rat Aorta and Expression in Vascular Smooth Muscle Cells

Angiotensin II (Ang II) is the main mediator of the Renin-Angiotensin-System acting on AT1 and other AT receptors. It is regarded as a pleiotropic agent that induces many actions, including functioning as a growth factor, and as a contractile hormone, among others. The aim of this work was to examine the impact of Ang II on the expression and function of α1-adrenergic receptors (α1-ARs) in cultured rat aorta, and aorta-derived smooth muscle cells. Isolated Wistar rat aorta was incubated for 24 h in DMEM at 37˚C, then subjected to isometric tension and to the action of added norepinephrine, in concentration-response curves. Ang II was added (1 × 10−5 M), and in some experiments, 5-Methylurapidil (α1A-AR antagonist), AH11110A (α1B-AR antagonist), or BMY-7378 (α1D-AR antagonist), were used to identify the α1-AR involved in the response. Desensitization of the contractile response to norepinephrine was observed due to incubation time, and by the Ang II action. α1D-AR was protected from desensitization by BMY-7378;while RS-100329 and prazosin partially mitigated desensitization. In another set of experiments, isolated aorta-derived smooth muscle cells were exposed to Ang II and α1-ARs proteins were evaluated. α1D-AR increased at 30 and 60 min post Ang II exposure, the α1A-AR diminished from 1 to 4 h, while α1B-AR remained unchanged over 24 h of Ang II exposure. Ang II induced an increase of α1D-AR at short times, and BMY-7378 protected α1D-AR from desensitization.

Effect of Microinfusion of Angiotensin Ⅱ into the RVLM in Rats on the Baroreceptor Reflex Sensitivity

Objective: The present study was designed to investigate the effect of microinfusion angiotensin Ⅱ(Ang Ⅱ),Ang Ⅱ type 1(AT_1)receptor antagonist losartan into the rostral ventrolateral medulla(RVLM)on the baroreceptor reflex sensitivity(BRS)in urethane-anesthetized rats. Methods: Reflex changes in heart rate(HR)were elicited by bolus intravenous injection of phenylephrine before and during RVLM microinfusion of saline(0.5 μl/h),Ang Ⅱ (1.5 nmol/h),losartan(250 nmol/h),and Ang Ⅱ(1.5 nmol/h)pretreated with microinjection of losartan (50 nmol/0.51 μl)into the RVLM.The average ratio between changes in HR in beats per minute(beats·min -1)and changes in mean arterial pressure [MAP,mmHg(1 mmHg=0.133 kPa)] was used as an index of BRS. Results: Ang Ⅱ resulted in a significant decrease in the BRS for reflex bradycardia compared with control(-2.1±0.1 vs-3.9±0.4 beats·min -1·mmHg -1).Microinfusion of losartan had no significant effect on BRS for reflex bradycardia.The effect of Ang Ⅱ was almost completely abolished by pretreatment with microinjection of losartan. Conclusion:These results showed that the exogenous Ang Ⅱ in the RVLM produces inhibitory modulation of BRS,which is mediated by AT_1 receptor.However,AT_1 receptor in the RVLM is not involved in the tonic control of BRS.

EFFECT OF ANGIOTENSIN II RECEPTOR ANTAGONIST AND ENDOTHELIN RECEPTOR ANTAGONIST ON NITROGLYCERIN TOLERANCE IN RATS

Objective. To investigate whether angiotensin II receptor antagonist and endothelin receptor antagonist can improve the nitroglycerin (Nit) tolerance in vivo. Methods. Twenty- four rats were divided into 4 groups (n=6,each): Control group, Nitroglycerin (Nit) group, Nit＋ bosentan group and Nit＋ losartan group. Nitroglycerin tolerance was induced by 2- day treatment of nitroglycerin patch (0.05 mg/h). AngiotensinⅡ receptor antagonist losartan ( 10 mg· kg－ 1· d－ 1 ) and endothelin receptor antagonist bosentan ( 100 mg· kg－ 1· d－ 1 ) were given by gavage for 2 days respectively. Results. The least hypotensive response to sodium nitroprusside (SNP) was observed in Nit group . The effective percentages of hypotensive response to SNP were increased in both Nit＋ losartan group and Nit＋ bosentan group compared with Nit group [(31.95± 4.45 )％ vs (21.00± 3.69 )％ , P< 0.01 and (33.18± 6.16 )％ vs (21.00± 3.69 )％ , P< 0.01 ,respectively]. The maximal vessel relaxation induced by SNP was the same in 4 different groups but the highest EC50 (concentration which produces 50％ of the maximal response to SNP) was found in tolerant group[(34± 10) nmol/ L,P < 0.01 .The ET- 1 amounts in plasma and vascular tissue were markedly increased by 54％ and 60％ in Nit group compared with those in control group(P< 0.01).The ET- 1 amounts in plasma and vascular tissue were decreased by 30％ and 37％ in Nit＋ losartan group compared with those in Nit group (P< 0.01). Conclusion. Endothelin receptor antagonist and angiotensinⅡ receptor antagonist could prevent against the Nit tolerance .

MicroRNA-155 mediates endogenous angiotensin II type 1 receptor regulation:implications for innovative type 2 diabetes mellitus management

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.

Cardioprotective Effect of Angiotensin n Receptor Antagonist on Perfused Ischemic Reperfusion Injury of Whole Isolated Rat Hearts

Objectives Investigated the cardioprotective and mechanisms of losartan on whole isolated ischemic reperfused rat heart. Methods Langendorff perfused systems was used to investigate losartan effect on whole isolated rat hearts in CPK, LDH, MDA, SOD, ang II and arrhythmia. Results Losartan decreased incidence of arrhythmia, improved atrial ventricular block recovery in reperfu-sion period, during ischemic period, CPK and LDH in I/R group increased significantly compared with control group, 51. 33±27. 02 vs 22. 42 ± 13. 33, 31. 80 ±4.56 vs 22. 28 ± 15. 96, respectively, but greatly decreased in losartan group compared with I/R group, 23. 90±21.74 vs 51. 33 ±27. 02 and 11. 50 ±13. 20 vs 31. 80 ±4. 56, respectively. During reperfusion period CPK, LDH increased significantly in I/R group compared with control group, 49. 11 ± 20. 63 vs 12. 14 ±5.92 and 28. 70±4. 69 vs 23. 10±21. 38, respectively, but decreased greatly in losartan group compared with I/R group, 39. 40 ± 9. 60 vs 49. 11 ± 20.63 and 14. 50 ±13. 75 vs 28. 70±4. 69. The content of MDA, ang II in I/R group myocytes is higher than control group's , 26. ± 9. 25 vs 17. 2 ± 3. 37 and 8. 43 ± 3. 81 vs 4. 80 ± 0. 20. However the content of SOD in two groups has no significantly change, 148. 20 ± 8. 72 vs 145. 08±6. 82. the content of MDA in losartan group myocardial tissue is much lower than control group, 15.92±4.05 vs 26. 80 ± 9. 25 and the content of ang II in losartan group myocardial tissue is much higher than I/R group, 12. 44 ± 6. 09 vs 8. 43 ± 3. 21. The department of cardiology of second hospital of Tianjin medical u-niversity Tianjin 300211 However, SOD has no significant change in two groups, 143. 47±7. 91 vs 145. 08 ± 6. 82. Conclusions Losartan against is-chemic - reperfusion injury of whole isolated rat hearts, those beneficial effects are mediate primarily by the inhibited of angiotensin II binding with its receptor and inhibited oxygen free radical scavenging potential.

POLYMORPHISM OF ANGIOTENSIN I TYPE 1 RECEPTOR GENE IN ELDERLY PATIENTS WITH ESSENTIAL HYPERTENSION

Objective To detect the A/C1165 polymorphism of angiotensin Ⅱ type Ⅰ receptor (AT1-R)gene in essential hypertensive elderly. Methods The A/C1166 polymorphism of AT1-R gene was assessed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in a case-control study of 87 essential hypertensive elders (EH) and 55 normolensive elders (NT). Results The genotype frequencies of AA, AC, CC were 0 .805 , 0.161, 0 .034 in EH group and 0 .927 ,0 .073 ,0 .000 in NT group respectively. The frequency of C61166 allele was higher in EH group (0.115) than in NT group (0 .036 )(P<0 .05 ). Conclusion The resultsindicate that A/C1166 polymorphism of AT1-R gene may be associated with essential hypertension in elderly.

Association of Polymorphisms in Angiotensin-converting Enzyme and Type 1 Angiotensin Ⅱ Receptor Genes with Coronary Heart Disease and the Severity of Coronary Artery Stenosis

To explore the relation of angiotensin-converting enzyme （ACE） and angiotensin Ⅱ type 1 receptor （AT1R） gene polymorphism with coronary heart disease （CHD） and the severity of coronary artery stenosis, 130 CHD patients who underwent coronary angiography were examined for the number of affected coronary vessels （≥75% stenosis） and coronary Jeopardy score. The insertion/deletion of ACE gene polymorphism and AT1R gene polymorphism （an A→C transversion at nucleotide position 1166） were detected by using polymerase chain reaction （PCR） and restriction fragment length polymorphism （RFLP） in CHD patients and 90 healthy serving as controls. The resuits showed that DD genotype and of ACE were more frequent in CHD patients than that in control group （38.5% vs 14.4%, P〈0.001）. The frequency of the ATIR A/C genotypes did not differ between the patients and the controls （10% vs 13.1%, P〉0.05）. The relative risk associated with the ACE-DD was increased by AT1R-AC genotype. Neither the number of affected coronary vessels nor the coronary score differed among the ACE I/D genotypes （P〉0.05）. But the number of affected coronary vessels and the coronary score were significantly greater in the patients with the AT1R-AC genotype than in those with the AA genotype （P〈0.05）. In conclusion, DD genotype may be risk factor for CHD and MI in Chinese people, and is not responsible for the development of the coronary artery stenosis. The AT1R-C allele may increase the relative risk associated with the ACE-DD genotype, and may be involved in the development of the stenosis of coronary artery.

Effect of angiotensin Ⅱ type 1 receptor blocker and angiotensin converting enzyme inhibitor on the intraocular growth factors and their receptors in streptozotocin-induced diabetic rats

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.

Construction of shRNA Targeted to the Rat Angiotensin Ⅱ Type 1 Receptors and Its RNAi in Cytoplasma

The expression vector of shRNA targeted to the rat angiotensin Ⅱ receptor gene was constructed and the efficacy of siRNAs to modulate the expression of target gene in the in vitro cultured mammalian cells was investigated for antihypertensive therapy in spontaneous hypertensive rat （SHR） at post-transcriptional level. The sense and antisense RNA oligonucleotides strands targeting angiotensin Ⅱ receptor mRNA were synthesized individually according to the sequence of the rat angiotensin Ⅱ receptor. For preparation of duplexes, sense- and antisense-stranded oligonucleotides were mixed and annealed, and the annealed duplexes were cloned into the pGenesil-1 vector. The rat glioma cells were transfected with constructed pGenesil-1-shRNA plasmid and scrambled plasmid. The cultured cells were collected at different phases. RT-PCR and Western blot were performed. The AT1 mRNA and protein levels behaved ultimately same. Compared to control after 48 h, AT1 mRNA levels were decreased to 35.5%±3.0 %, and the levels reached their lowest point after 72 h （20.7% ±4 % of control）. At 24 and 48 h, AT1 protein was reduced to 46.9%±4.2% and 36.98%±3.7% respectively compared to control and a maximum reduction was observed after 72 h of incubation （28.1%± 4% compared to controls）. Plasmid-based shRNA expression systems targeted against the rat angiotensin Ⅱ receptor gene were generated successfully. The shRNAs with a 22-nt stem and a short loop were cleaved into small interfering dsRNA （siRNA） by the Dicer. The in vitro transcribed siRNA enables the effective silencing of gene expression to the target mRNA and leads to effective inhibition of translation of proteins and will be lay the foundation of application of gene silencing technology to hypertensive rats.

Expression of Angiotensin Ⅱ Receptors in Aldosterone-producing Adenoma of the Adrenal Gland and Their Clinical Significance

The expression of angiotensin Ⅱ type 1 receptor (AT1R) and angiotensin Ⅱ type 2 receptor (AT2R) in aldosterone-producing adenoma (APA) of the adrenal gland was detected, and their relationship with clinical indexes of APA was analyzed. The mRNA expression of AT1R and AT2R in 50 cases of APA and tissues adjacent to tumors and 12 cases of normal adrenal tissues was detected by using reverse transcriptase polymerase chain reaction (RT-PCR). The expression of AT1R and AT2R proteins in paraffin-embedded slices of tissue was detected by immunohistochemistry. The expression of AT1R in adenoma, tissues adjacent to tumor, and normal tissues of the adrenal gland showed no significant differences. The expression of AT2R in APA tissue was lower than that in normal adrenal gland tissues (P<0.05). Correlation analysis of the mRNA expression level of AT2R and clinical data from patients demonstrated that AT2R expression was negatively related to plasma aldosterone concentration (PAC) (r=-0.467, P<0.05), but positively related with plasma renin activity (PRA) (r=0.604, P<0.05). It is concluded that down-regulation of the AT2R expression is possibly related with the tumorigenesis of APA.

Effect of nuclear factor-κB and angiotensin Ⅱ receptor type 1 on the pathogenesis of rat non-alcoholic fatty liver disease

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.

Effects of chronic peripheral pretreatment with an angiotensin II type-1 receptor blocker on apoptosis-related molecules in rats with cerebral ischemia/reperfusion injury

Chronic systemic treatment with blockers of angiotensin II type-1 （AT1） receptors inhibits ischemia-induced apoptosis and reduces ischemic neuronal damage. However, the molecular mechanisms of AT1 receptor blockers in modulating neuronal apoptosis remain poorly understood. Pretreatment with irbesartan significantly suppressed cell apoptosis at 1-7 days following cerebral ischemia/reperfusion, increased levels of brain-derived neurotrophic factor, and elevated the ratios of Bcl-2/Bax and phosphorylated cyclic adenosine monophosphate response element-binding protein （pCREB）/CREB in the ischemic cortex at 1 day after reperfusion, as well as suppressing caspase-3 activation. Cerebral ischemia increased the mRNA expression of AT1 and AT2 receptors in the ischemic cortex, whereas irbesartan blocked this increase in AT1 expression but potentiated the expression of AT2. Therefore, this AT1 receptor blocker was neuroprotective by increasing the ratios of Bcl-2/Bax and pCREB/CREB, increasing brain-derived neurotrophic factor levels, inhibiting caspase-3 activation, and modulating AT receptor expression.

Spectrofluorimetric method for determination of some angiotensin II receptor antagonists

A simple, rapid, accurate and highly sensitive spectrofluorimetric method has been developed for determination of some angiotensin II receptor antagonists (AIIRA’s), namely Losartan potassium (Los-K), Irbesartan (Irb), Valsartan (Val) and Candesartan cilexetil (Cand) in pure forms as well as in their pharmaceutical dosage forms. All the variables affecting the relative fluorescence intensity (RFI) were studied and optimized. Under the optimum conditions, linear relationships with good correlation coefflcients (0.9982–0.9991) were obtained over the concentration range from 0.006 mg/mL to 1.7 mg/mL. Good accuracy and precision were successfully obtained for the analysis of tablets containing each drug alone or combined with hydrochlorothiazide (HCTZ) without interferences from the co-formulated HCTZ or the additives commonly present in tablets.

Effects of angiotensin Ⅱ receptor antagonist, Losartan on the apoptosis, proliferation and migration of the human pancreatic stellate cells

AIM： To investigate the effects of AT, （Type 1 angiotensin Ⅱ receptor） antagonist （Losartan） on the apoptosis, proliferation and migration of the human pancreatic stellate cells （hPSCs）. METHODS： hPSCs were isolated from pancreatic sample of patients with pancreatic carcinoma using radioimmunoassay （RIA） technique to detect the concentration of AngⅡ in culture media and cell homogenate. Immunocytochemistry （ICC） and in situ hybridization （ISH） methods were utilized to test AT1 expression in hPSCs. Effects of Losartan on hPSCs proliferation, apoptosis and migration were investigated using BrdU incorporation, TUNEL, flow cytometry （FCM）, and phase-contrast microscope separately when cells treated with Losartan. Immunofluorescence and Western blot were applied to quantify the expression of type Ⅰ collagen in hPSCs. RESULTS： There exists AT1 expression in hPSCs, while no AngⅡ was detected in culture media and cell homogenate. Losartan induces cell apoptosis in a doseand time-dependent manner （apparently at 10^-5 mol/L）, no pro-proliferative effect was observed in the same condition. Corresponding dosage of Losartan can also alleviate the motion capability and type Ⅰ collagen content of hPSCs compared with AngⅡ treatment and non-treatment control groups. CONCLUSION： These findings suggest that paracrine not autocrine functions of AngⅡ may have effects on hPSCs, which was mediated by AT1 expressed on cells, while Losartan may exert anti-fibrotic effects by inhibiting hPSCs motion and partly by inducing apoptosis.

Effects of angiotensin-converting enzyme inhibitor and angiotensin Ⅱ receptor blocker on one-year outcomes of patients with atrial fibrillation: insights from a multicenter registry study in China

Objective To evaluate the effect of angiotensin-converting enzyme inhibitor(ACEI)/angiotensin Ⅱ receptor blocker(ARB)therapy on the prognosis of patients with atrial fibrillation(AF).Methods A total of 1,991 AF patients from the AF registry were divided into two groups according to whether they were treated with ACEI/ARB at recruitment.Baseline characteristics were carefully collected and analyzed.Logistic regression was utilized to identify the predictors of ACEI/ARB therapy.The primary endpoint was all-cause mortality,while the secondary endpoints included cardiovascular mortality,stroke and major adverse events(MAEs)during the one-year follow-up period.Univariable and multivariable Cox regression were performed to identify the association between ACEI/ARB therapy and the one-year outcomes.Results In total,759 AF patients(38.1%)were treated with ACEI/ARB.Compared with AF patients without ACEI/ARB therapy,patients treated with ACEI/ARB tended to be older and had a higher rate of permanent AF,hypertension,diabetes mellitus,heart failure(HF),left ventricular ejection fraction(LVEF)<40%,coronary artery disease(CAD),prior myocardial infarction(MI),left ventricular hypertrophy,tobacco use and concomitant medications(all P<0.05).Hypertension,HF,LVEF<40%,CAD,prior MI and tobacco use were determined to be predictors of ACEI/ARB treatment.Multivariable analysis showed that ACEI/ARB therapy was associated with a significantly lower risk of one-year all-cause mortality[hazard ratio(HR)(95%CI):0.682(0.527-0.882),P=0.003],cardiovascular mortality[HR(95%CI):0.713(0.514-0.988),P=0.042]and MAEs[HR(95%CI):0.698(0.568-0.859),P=0.001].The association between ACEI/ARB therapy and reduced mortality was consistent in the subgroup analysis.Conclusions In patients with AF,ACEI/ARB was related to significantly reduced one-year all-cause mortality,cardiovascular mortality and MAEs despite the high burden of cardiovascular comorbidities.

DNA methylation of angiotensin Ⅱ receptor gene in nonalcoholic steatohepatitis-related liver fibrosis

AIM To clarify whether Agtr1 a methylation is involved in the development of nonalcoholic steatohepatitis(NASH)-related liver fibrosis in adult rats.METHODS A choline-deficient amino acid(CDAA) diet model was employed for methylation analysis of NASH-related liver fibrosis.Agtr1 a methylation levels were measured in the livers of CDAA- and control choline-sufficient amino acid(CSAA)-fed rats for 8 and 12 wk using quantitative methylation-specific PCR.Hepatic stellate cells(HSCs) were isolated by collagenase digestion of the liver,followed by centrifugation of the crude cell suspension through a density gradient.Agtr1 a methylation and its gene expression were also analyzed during the activation of HSCs.RESULTS The mean levels of Agtr1 a methylation in the livers of CDAA-fed rats(11.5% and 18.6% at 8 and 12 wk,respectively) tended to be higher(P = 0.06 and 0.09,respectively) than those in the livers of CSAA-fed rats(2.1% and 5.3% at 8 and 12 wk,respectively).Agtr1 a was not methylated at all in quiescent HSCs,but was clearly methylated in activated HSCs(13.8%,P < 0.01).Interestingly,although Agtr1 a was hypermethylated,the Agtr1 a m RNA level increased up to 2.2-fold(P < 0.05) in activated HSCs compared with that in quiescent HSCs,suggesting that Agtr1 a methylation did not silence its expression but instead had the potential to upregulate its expression.These findings indicate that Agtr1 a methylation and its upregulation of gene expression are associated with the development of NASH-related liver fibrosis.CONCLUSION This is the first study to show that DNA methylation is potential y involved in the regulation of a renin-angiotensin system-related gene expression during liver fibrosis.

Origin and genomic characteristics of SARS-CoV-2 and its interaction with angiotensin converting enzyme type 2 receptors, focusing on the gastrointestinal tract

The emergence of coronavirus disease-2019 induced by a newly identified bcoronavirus, namely severe acute respiratory syndrome coronavirus 2(SARSCoV-2) has constituted a public health emergency. Even though it was considered a zoonotic disease, the virus has also spread among humans via respiratory secretions. The expression and distribution of angiotensin converting enzyme type 2(ACE2) in various human organs might also show other possible infection routes. High ACE2 ribonucleic acid expression has been identified in the gastrointestinal tract(GI) indicating its importance as a possible infection pathway of SARS-CoV-2. ACE2 induces viral entry into the host and most importantly has been found to be associated with the function of the gut. Its deficiency has been implicated in several pathologies such as colorectal inflammation. The renin-angiotensin system(RAS) is an essential regulatory cascade operating both at a local tissue level and at the systemic or circulatory level. The RAS may be important in the pathogenesis of chronic liver disease and is associated with the up-regulation of ACE2. Thus, the aim of this review is firstly, the analysis of some important general and genome characteristics of SARS-CoV-2 and secondly, and most importantly, to focus on the utility of ACE2 receptors in both SARS-CoV-2 replication and pathogenesis, especially in the GI tract.

Hyperkalemia of Angiotensin-converting Enzyme Inhibitors or Angiotensin Receptor Blockers in Hemodialysis: A Meta-analysis

The safety of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) used in hemodialysis (HD) patients was evaluated.Medline,Embase,the Cochrane Library,some databases of clinical trial registries,grey literatures,other reference lists of eligible articles and review articles for the randomized clinical trials (RCTs) on comparison of ACEIs/ARBs or placebo in HD patients were retrieved.RCTs reporting the risk of hyperkalemia by using ACEIs/ARBs in HD patients were selected.Eight articles met the eligibility criteria and were subjected to meta-analysis by using the Cochrane Collaboration’s RevMan 4.2 software package.The results showed that there was no significant difference in hyperkalemia in HD patients between ACEIs or ARBs group and control group (ACEIs vs.control:RD=0.03,95% CI=-0.13?0.18,Z=0.34,P=0.73;ARBs vs.control:RD=-0.02,95% CI=-0.07?0.03,Z=0.75,P=0.45).However,there was no significant difference in the serum potassium between ACEIs or ARBs group and control group in HD patients (ACEIs vs.control:WMD=0.10,95% CI=0.06?0.15,Z=4.64,P<0.00001;ARBs vs.control:WMD=-0.24,95% CI=-0.37--0.11,Z=3.58,P=0.0003).The use of ACEIs or ARBs could not cause an increased risk of hyperkalemia in HD patients,however the serum potassium could be increased with use of ACEIs in HD patients.Therefore the serum potassium concentration should still be closely monitored when ACEIs are taken during the maintenance HD.