A historical literature review of coronary microvascular obstruction and intra-myocardial hemorrhage as functional/structural phenomena

The analysis of experimental data demonstrates that platelets and neutrophils are involved in the no-reflow phenomenon,also known as microvascular obstruction(MVO).However,studies performed in the isolated perfused hearts subjected to ischemia/reperfusion(I/R)do not suggest the involvement of microembolization and microthrombi in this phenomenon.The intracoronary administration of alteplase has been found to have no effect on the occurrence of MVO in patients with acute myocardial infarction.Consequently,the major events preceding the appearance of MVO in coronary arteries are independent of microthrombi,platelets,and neutrophils.Endothelial cells appear to be the target where ischemia can disrupt the endothelium-dependent vasodilation of coronary arteries.However,reperfusion triggers more pronounced damage,possibly mediated by pyroptosis.MVO and intra-myocardial hemorrhage contribute to the adverse post-infarction myocardial remodeling.Therefore,pharmacological agents used to treat MVO should prevent endothelial injury and induce relaxation of smooth muscles.Ischemic conditioning protocols have been shown to prevent MVO,with L-type Ca2+channel blockers appearing the most effective in treating MVO.

The effect of an adaptation to hypoxia on cardiac tolerance to ischemia/reperfusion

The acute myocardial infarction(AMI)and sudden cardiac death(SCD),both associated with acute cardiac ischemia,are one of the leading causes of adult death in economically developed countries.The development of new approaches for the treatment and prevention of AMI and SCD remains the highest priority for medicine.A study on the cardiovascular effects of chronic hypoxia(CH)may contribute to the development of these methods.Chronic hypoxia exerts both positive and adverse effects.The positive effects are the infarct-reducing,vasoprotective,and antiarrhythmic effects,which can lead to the improvement of cardiac contractility in reperfusion.The adverse effects are pulmonary hypertension and right ventricular hypertrophy.This review presents a comprehensive overview of how CH enhances cardiac tolerance to ischemia/reperfusion.It is an in-depth analysis of the published data on the underlying mechanisms,which can lead to future development of the cardioprotective effect of CH.A better understanding of the CH-activated protective signaling pathways may contribute to new therapeutic approaches in an increase of cardiac tolerance to ischemia/reperfusion.

60d头低位卧床实验间中药对心血管控制的影响(英文)

目的本研究旨在通过头低位卧床60d试验,探讨中草药方剂太空养心丸(Tai Kong Yang Xin Prescription)对心血管自主神经功能控制及动脉压力反射功能的影响。方法14名健康志愿者,随机分为对照组(7名)和中草药治疗组(7名)。在卧床试验前、中、后,对志愿者的心血管变异性和动脉压力反射敏感度进行了详细评估。结果所有志愿者的心率都随卧床期的延长而逐步升高,并且在卧床后恢复期的第12天仍未恢复到卧床前的基础水平;平均动脉压也在卧床试验过程中逐渐升高,但在卧床结束后的第12天缓慢恢复到卧床前的水平;压力反射敏感度和呼吸性窦性心律不齐在卧床试验中明显下降,且在卧床结束后的恢复期仍保持很低水平;动脉收缩压的低频功率在卧床试验开始后升高,该值在整个卧床期及卧床后的恢复期均保持着较高的水平。虽然上述变化在对照组和中草药治疗组中没有显著性差异,并且两组的压力反射最佳延迟时间在卧床后均明显增加,但是在卧床期结束后的第12天,压力反射最佳延迟时间只在中草药治疗组中出现了部分的恢复。结论本研究首次探讨了太空养心丸对人体心脏自主神经功能影响的评价。研究结果表明该方剂对志愿者在模拟失重试验结束后的动脉压力反射最佳延迟时间的恢复有明显的帮助。

RGD刺激整联蛋白增加心肌细胞对大分子物质的摄取

目的探讨刺激新生大鼠心肌细胞(NRCMs)整联蛋白增加某些大分子物质的摄取及其机制。方法以100～300mg/L甘氨酸-精氨酸-甘氨酸-天冬酰胺-色氨酸序列(RGD)刺激NRCMs整联蛋白,同时加入不同浓度德克萨斯红标记的卵蛋白(OTR)、右旋糖苷(DTR),孵育8h、16h、24h,应用免疫荧光技术研究心肌细胞对OTR、DTR的摄取及Dysferlin面积。结果 RGD增加NRCMs对OTR、DTR的摄取(与对照组比较P<0.001,P<0.05),并与孵育时间呈正相关(P<0.001),OTR的摄取与其浓度呈正相关(P<0.001)。RGD组Dysferlin面积为无RGD组的3倍。RGD刺激非搏动的心肌细胞,不增加OTR、DTR的摄取,亦不增加Dysferlin面积。结论 RGD刺激增加NRCMs对OTR、DTR的摄取。Dysferlin参与RGD诱导的心肌细胞膜损伤的修复过程。RGD诱导的心肌细胞膜损伤与细胞的收缩活动相关。

Standardizing a simpler, more sensitive and accurate tail bleeding assay in mice

AIM: To optimize the experimental protocols for a simple, sensitive and accurate bleeding assay.METHODS: Bleeding assay was performed in mice by tail tip amputation, immersing the tail in saline at 37 ℃, continuously monitoring bleeding patterns and measuring bleeding volume from changes in the body weight. Sensitivity and extent of variation of bleeding time and bleeding volume were compared in mice treated with the P2 Y receptor inhibitor prasugrel at various doses or in mice deficient of Fc Rγ, a signaling protein of the glycoprotein VI receptor.RESULTS: We described details of the bleeding assay with the aim of standardizing this commonly used assay. The bleeding assay detailed here was simple to operate and permitted continuous monitoring of bleedingpattern and detection of re-bleeding. We also reported a simple and accurate way of quantifying bleeding volume from changes in the body weight, which correlated well with chemical assay of hemoglobin levels(r2 = 0.990, P < 0.0001). We determined by tail bleeding assay the dose-effect relation of the anti-platelet drug prasugrel from 0.015 to 5 mg/kg. Our results showed that the correlation of bleeding time and volume was unsatisfactory and that compared with the bleeding time, bleeding volume was more sensitive in detecting a partial inhibition of platelet's haemostatic activity(P < 0.01). Similarly, in mice with genetic disruption of Fc Rγ as a signaling molecule of P-selectin glycoprotein ligand-1 leading to platelet dysfunction, both increased bleeding volume and repeated bleeding pattern defined the phenotype of the knockout mice better than that of a prolonged bleeding time.CONCLUSION: Determination of bleeding pattern and bleeding volume, in addition to bleeding time, improved the sensitivity and accuracy of this assay, particularly when platelet function is partially inhibited.

HMGB1 induces secretion of matrix vesicles which participate in microcalcification of atherosclerotic plaques

AIM: Early calcification of atherosclerotic plaques are colocalized with macrophage and high mobility group box 1( HMGB1),a cytokine associated with biomineralizing process under physiological and pathological conditions. Our study aims to evaluate whether HMGB1 induces ectopic mineralization via promoting the secretion of matrix vesicles( MVs) from macrophages. METHODS: HMGB1 was added to the medium of macrophages,the secretion of MVs in the supernatant was tested by flow cytometry analysis. The mineral deposition in calcifying medium was detected by Alizarin Red staining and von Kossa staining. Transmission electron microscopy showed the formation of hydroxyapatite crystals in MVs. Then we subcutaneous injection into mice with MVs to induce regional mineralization. RESULTS: HMGB1 significantly promoted secretion of MVs from macrophages as raveled by flow cytometry analysis. TNAP activity,considered as a marker of MVs maturation,was higher in HMGB1-induced MVs compared to the control-MVs. HMGB1-MVs also led to mineral deposition in an in vitro MVs-collagen mineralization model. Subcutaneous injection into mice with MVs derived from HMGB1-treated cells showed a greater potential to initiate regional mineralization. Mechanistic experiments revealed that HMGB1 activated neutral sphingomyelinase 2( n SMase2) that involved the receptor for advanced glycation end products( RAGE) and p38MAPK( upstream of n SMase2). Inhibition of n SMase2 with GW4869 or p38 MAPK with SB-239063 prevented MVs secretion and mineral deposition. CONCLUSIONS: HMGB1 induces MVs secretion from macrophages at least in part,via the RAGE / p38 MAPK /n SMase2 signaling pathway. Our findings thus reveal a novel mechanism by which HMGB1 may participated in the early calcification of atherosclerotic plaques.

Pyroptosis is a drug target for prevention of adverse cardiac remodeling: The crosstalk between pyroptosis, apoptosis, and autophagy

Acute myocardial infarction(AMI)is one of the main reasons of cardiovascular disease-related death.The introduction of percutaneous coronary intervention to clinical practice dramatically decreased the mortality rate in AMI.Adverse cardiac remodeling is a serious problem in cardiology.An increase in the effectiveness of AMI treatment and prevention of adverse cardiac remodeling is difficult to achieve without understanding the mechanisms of reperfusion cardiac injury and cardiac remodeling.Inhibition of pyroptosis prevents the development of postinfarction and pressure overload-induced cardiac remodeling,and mitigates cardiomyopathy induced by diabetes and metabolic syndrome.Therefore,it is reasonable to hypothesize that the pyroptosis inhibitors may find a role in clinical practice for treatment of AMI and prevention of cardiac remodeling,diabetes and metabolic syndrome-triggered cardiomyopathy.It was demonstrated that pyroptosis interacts closely with apoptosis and autophagy.Pyroptosis could be inhibited by nucleotide-binding oligomerization domain-like receptor with a pyrin domain 3 inhibitors,caspase-1 inhibitors,microRNA,angiotensin-converting enzyme inhibitors,angiotensinⅡreceptor blockers,and traditional Chinese herbal medicines.

利用非线性方法研究头低位卧床对心血管调控机制的影响(英文)

目的本研究旨在用非线性分析方法,探讨-6°头低位卧床试验对心血管调控机制的影响,并将对照组和中药组进行比较。方法 14名男性健康志愿者随机分入对照组和中药组,进行60d的头低位卧床试验。在试验前、中、后,运用非线性分析技术对心率变异、血压变异进行测试。结果志愿者心率水平在卧床开始后的前21d保持稳定,但从卧床试验的第41天起显著升高,且在卧床结束后亦未恢复至正常;趋向波动指数(DFAα1)于卧床试验开始后的第2天出现明显升高,且维持升高状态至试验结束后的第12天;混沌指数(chaos)在卧床过程中明显下降。卧床试验过程中组间对比发现:对照组心率变异的1/f以及血压变异的SDNN、LF/HF、DFAα1和1/f明显高于中药组,并且心率变异的DFAα2和血压变异的HF明显降低。结论在卧床试验后期机体出现迷走神经张力下降,迷走交感平衡升高;而中药可以减轻模拟失重对心血管系统的影响。

Uridine adenosine tetraphosphate acts as a pro-angiogenic factor in vitrothrough purinergic P2Y receptors

OBJECTIVE Uridine adenosine tetraphosphate(Up4A),a dinucleotide,contains both purine and pyrimidine moieties,and exerts its vascular influence via activation of purinergic receptors.Here,we aimed to investigate the effects of Up4 A on angiogenesis and the putative purinergic receptors(PR)involved in this process.METHODS Tubule formation assay was performed in 3D matrix system.In this assay,human umbilical vein endothelial cells(HUVECs)were co-cultured with pericytes with various Up4 A doses(0,1,2.5,5,10 and 20μmol·L-1)in the absence and presence of P2Y6 R antagonist MRS2578(10μmol·L-1)for 5d.Expression profile of PR subtypes and angiogenic factors was assessed in HUVECs by q-PCR with and without P2Y6 R antagonist.RESULTS No difference in initial tubule formation was detected between Up4 A stimulation and control conditions at day 2.In contrast,a significant increase in vascular density in response to Up4 A was observed at day 5.Up4 A at a dose of 2.5and 5μmol·L-1 promoted total tubule length(by-1.89 fold and-2.23fold),number of tubules(by-1.71 fold and-1.89fold)as well as number of junctions(by-2.24 fold and-2.80fold),all of which were inhibited by MRS2578.Further increase in Up4 A dose to10 and 20μmol·L-1 did not induce an increase in these vascular parameters as compared to non-treated controls.Moreover,Up4 A increased mRNA level of P2YRs(P2Y2R,P2Y4 R and P2Y6R)but not P2XR(P2X4R and P2X7R)or P1R(A2AR and A2BR),while Up4 A upregulated VEGFA and ANGPT1 but not VEGFR2,ANGPT2,Tie1 and Tie2at mRNA level.Transcriptional upregulation of P2 YRs and angiogenic factors by Up4 A was inhibited by MRS2578.CONCLUSION Up4 A is functionally capable of promoting tubule formation in vitro co-culture system.This process is likely mediated by activation of pyrimidine-favored P2 YRs but not P2 XR or P1 Rs,and involves stimulation of well known angiogenic factors.

Inherited Wolff–Parkinson–White Syndrome

Wolff-Parkinson-White(WPW)syndrome is a congenital disorder of cardiac conduction system characterized by electrocardiographic preexcitation and episodes of paroxysmal supraventricular tachycardia.It is caused by a cardiac developmental defect in the electrical insulation between the atria and the ventricles due to the presence of an accessory pathway.WPW syndrome is a common cause of supraventricular tachycardia with benign prognosis.However,this clinical entity also predisposes patients to an increased risk of sudden cardiac death,especially in the setting of preexcited atrial fibrillation.WPW syndrome is usually sporadic and of unknown etiology in most cases.During the past10years,a signifi cant heritable factor is increasingly recognized.Identifi cation of the genetic basis among patients with WPW syndrome has important implications for understanding the molecular mechanism of ventricular preexcitation and the development of therapeutic strategies for risk stratifi cation and management.The goal of this review is to examine the previous studies on hereditary variants,as well as to outline potential future avenues toward defi ning the heritability of WPW syndrome.

Circular RNAs in Cardiovascular Diseases:Regulation and Therapeutic Applications

Cardiovascular disease is one of the leading causes of mortality worldwide.Recent studies have shown that circular RNAs(circRNAs)have emerged as important players in the prevention and treatment of cardiovascular diseases.circRNAs are a class of endogenous noncoding RNAs that are generated by back-splicing and are involved in many pathophysiological processes.In this review,we outline the current research progress on the regulatory roles of circRNAs in cardiovascular diseases.Further,new technologies and methods available for identifying,validating,synthesizing,and analyzing circRNAs,as well as their applications in therapeutics,are highlighted here.Moreover,we summarize the increasing insights into the potential use of circRNAs as circulating diagnostic and prognostic biomarkers.Finally,we discuss the prospects and challenges of circRNA therapeutic applications for cardiovascular disease therapy,with a particular focus on developing circRNA synthesis and engineering delivery systems.

Cellular polyploidy in organ homeostasis and regeneration

Polyploid cells,which contain more than one set of chromosome pairs,are very common in nature.Polyploidy can provide cells with several potential benefits over their diploid counterparts,including an increase in cell size,contributing to organ growth and tissue homeostasis,and improving cellular robustness via increased tolerance to genomic stress and apoptotic signals.Here,we focus on why polyploidy in the cell occurs and which stress responses and molecular signals trigger cells to become polyploid.Moreover,we discuss its crucial roles in cell growth and tissue regeneration in the heart,liver,and other tissues.

Cell models with inducible oncogenic translocations allow to evaluate the potential of drugs to favor secondary translocations

Dear Editor,Chromosomal translocations result from the interchange of geneticmaterial between non-homologous chromosomes.Chromosomal translocations are formed by erroneous repair of double-stranded breaks(DSBs)via non-homologous end joining(NHEJ)[1].Some genotoxic drugs produce DSBs and thus present a major risk factor for the development of oncogenic chromosomal translocations.The risk factors that interfere with translocationprone DSB repair,once DSBs are already formed,are obscure,and potential effects of drugs on translocation formation during this step have never been explored.

Preserving cognitive function in patients with Alzheimer's disease:The Alzheimer's disease neuroprotection research initiative(ADNRI)

The global trend toward aging populations has resulted in an increase in the occurrence of Alzheimer's disease(AD)and associated socioeconomic burdens.Abnormal metabolism of amyloid-β(Aβ)has been proposed as a significant pathomechanism in AD,supported by results of recent clinical trials using anti-Aβantibodies.Nonetheless,the cognitive benefits of the current treatments are limited.The etiology of AD is multifactorial,encompassing Aβand tau accumulation,neuroinflammation,demyelination,vascular dysfunction,and comorbidities,which collectively lead to widespread neurodegeneration in the brain and cognitive impairment.Hence,solely removing Aβfrom the brain may be insufficient to combat neurodegeneration and preserve cognition.To attain effective treatment for AD,it is necessary to(1)conduct extensive research on various mechanisms that cause neurodegeneration,including advances in neuroimaging techniques for earlier detection and a more precise characterization of molecular events at scales ranging from cellular to the full system level;(2)identify neuroprotective intervention targets against different neurodegeneration mechanisms;and(3)discover novel and optimal combinations of neuroprotective intervention strategies to maintain cognitive function in AD patients.The Alzheimer's Disease Neuroprotection Research Initiative's objective is to facilitate coordinated,multidisciplinary efforts to develop systemic neuroprotective strategies to combat AD.The aim is to achieve mitigation of the full spectrum of pathological processes underlying AD,with the goal of halting or even reversing cognitive decline.

Post-infarct cardiac injury, protection and repair:roles of non-cardiomyocyte multicellular and acellular components

Following myocardial infarction(MI), cardiomyocytes and infarct size are the focus of our attention when evaluating the extent of cardiac injury, efficacy of therapies or success in repairing the damaged heart by stem cell therapy. Numerous interventions have been shown by pre-clinical studies to be effective in limiting infarct size, and yet clinical trials designed accordingly have yielded disappointing outcomes. The ultimate goal of cardiac protection is to limit the adverse cardiac remodeling. Accumulating studies have revealed that post-infarct remodeling can be attenuated without infarct size limitation. To reconcile this, one needs to appreciate the significance of various cellular and acellular myocardial components that, like cardiomyocytes, undergo significant damage and dysfunction, which impact the ultimate cardiac injury and remodelling. Microvascular injury following ischemia-reperfusion may influence infarct size and promote inflammation. Myocardial injury evokes innate immunity with massive inflammatory infiltration that, although essential for the healing process, exacerbates myocardial injury and damage to extracellular matrix leading to dilative remodeling. It is also important to consider the multiple non-cardiomyocyte components in evaluating therapeutic efficacy. Current research indicates the pivotal role of these components in achieving cardiac regeneration by cell therapy. This review summarizes findings in this field, highlights a broad consideration of therapeutic targets,and recommends cardiac remodeling as the ultimate target.

Effects of Traditional Chinese Medicine Shensong Yangxin Capsules on Heart Rhythm and Function in Congestive Heart Failure Patients with Frequent Ventricular Premature Complexes：A Randomized, Double-blind, Multicenter Clinical Trial

Background：Pharmacological therapy for congestive heart failure （CHF） with ventricular arrhythmia is limited.In the study,our aim was to evaluate the effects of Chinese traditional medicine Shensong Yangxin capsules （SSYX） on heart rhythm and function in CHF patients with frequent ventricular premature complexes （VPCs）.Methods：This double-blind,placebo-controlled,multicenter study randomized 465 CHF patients with frequent VPCs to the SSYX （n =232） and placebo groups （n =233） for 12 weeks of treatment.The primary endpoint was the VPCs monitored by a 24-h ambulatory electrocardiogram.The secondary endpoints included the left ventricular ejection fraction （LVEF）,left ventricular end-diastolic diameter,N-terminal pro-brain natriuretic peptide （NT-proBNP）,New York Heart Association （NYHA） classification,6-min walking distance （6MWD）,Minnesota Living with Heart Failure Questionnaire （MLHFQ） scores,and composite cardiac events （CCEs）.Results：The clinical characteristics were similar at baseline.SSYX caused a significantly greater decline in the total number of VPCs than the placebo did （-2145 ± 2848 vs.-841 ± 3411,P 〈 0.05）.The secondary endpoints of the LVEE NYHA classification,NT-proBNP,6MWD,and MLHFQ scores showed a greater improvements in the SSYX group than in the placebo group （ALVEF at 12th week：4.75 ± 7.13 vs.3.30 ± 6.53;NYHA improvement rate at the 8th and 12th week：32.6% vs.21.8%,40.5% vs.25.7%;mean level of NT-proBNP in patients with NT-proBNP 〉125 pg/ml at 12th week：-122 [Q1,Q3：-524,0] vs.-75 [Q1,Q3：-245,0];A6MWD at 12th week：35.1 ± 38.6 vs.17.2 ± 45.6;AMLHFQ at the 4th,8th,and 12th week：-4.24 ± 6.15 vs.-2.31 ± 6.96,-8.l 9 ± 8.41 vs.-3.25 ± 9.40,10.60 ± 9.41 vs.-4.83 ± 11.23,all P 〈 0.05）.CCEs were not different between the groups during the study period.Conclusions：In this 12-week pilot study,SSYX was demonstrated to have the benefits of VPCs suppression and cardiac function improvement with good compliance on a background of standard treatment for CHF.

Chemotactic signaling in mesenchymal cells compared to amoeboid cells

Cell chemotaxis plays a pivotal role in normal development,inflammatory response,injury repair and tissue regeneration in all organisms.It is also a critical contributor to cancer metastasis,altered angiogenesis and neurite growth in disease.The molecular mechanisms regulating chemotaxis are currently being identified and key components may be pertinent therapeutic targets.Although these components appear to be mostly common in various cells,there are important differences in chemotactic signaling networks and signal processing that result in the distinct chemotactic behavior of mesenchymal cells compared to much better studied amoeboid blood cells.These differences are not necessarily predetermined based on cell type,but are rather chosen and exploited by cells to modify their chemotactic behavior based on physical constraints and/or environmental conditions.This results in a specific type of chemotactic migration in mesenchymal cells that can be selectively targeted in disease.Here,we compare the chemotactic behavior,signaling and motility of mesenchymal and amoeboid cells.We suggest that the current model of chemotaxis is applicable for small amoeboid cells but needs to be reconsidered for large mesenchymal cells.We focus on new candidate regulatory molecules and feedback mechanisms that may account for mesenchymal cell type-specific chemotaxis.