ACE基因I/D多态性在心血管疾病中的研究进展

血管紧张素转化酶（ACE）是肾素-血管紧张素-醛固酮系统（RAAS）的关键酶，在心血管疾病发生发展中起重要作用。近年来有多个研究探讨ACE基因插入/缺失（insertion/ deletion,I/D）多态性与心血管疾病之间的关系，然研究结果尚存争议。本文主要就ACE基因I/D的多态性及其与心血管疾病关系的研究进展做一综述。     

p38 MAPK及基质金属蛋白酶在心力衰竭病人心肌重构中的意义

目的: 探讨不同程度心力衰竭病人心肌组织丝裂素活化蛋白激酶（p38 MAPK）、基质金属蛋白酶家族（MMP-2、3、9）、细胞外基质（ECM）纤连蛋白（FN）表达与心肌重构的关系。方法: 选择因二尖瓣关闭不全心脏病接受二尖瓣置换术的心力衰竭病人39例，正常对照8例来自意外伤亡的器官捐献者。光镜检查心肌组织病理变化;免疫沉淀法检测心肌组织p38 MAPK磷酸化，及p38 MAPK、MMP-2、3、9蛋白表达; 免疫荧光法检查心肌组织FN的分布。结果: 瓣膜病所致心力衰竭病人心肌组织呈典型的心肌重构病理改变。心力衰竭组心肌 p38 MAPK 磷酸化明显强于对照组（P<0.05），随心功能恶化，其表达逐渐增加（P<0.05或P<0.01）。 心力衰竭组心肌组织MMP-2、3、9蛋白表达明显强于正常对照组，各心力衰竭组与正常对照组相比差异显著（P<0.05或P<0.01）; 相反，心力衰竭组心肌组织FN蛋白表达明显弱于正常组，各心力衰竭组与正常对照组相比差异显著（P<0.05或P<0.01）。结论: 心力衰竭病人通过激活p38 MAPK诱导心肌细胞肥大、坏死，通过MMP-2、3、9表达量的增高降解心肌细胞外基质FN，共同参与心肌重构的病理过程而恶化心功能。     

心肌素在心脏发育及平滑肌细胞分化中的作用

2001年6月29日。在Cell杂志上Da-Zhi Wang等的研究小组首次报道了心肌素（myocardin）的发现。一种心肌和平滑肌特异性的血清应答因子（Serum response factor，SRF）的辅助因子。心肌素的发现促进了人们对心肌特异性转录机制的更为深入的了解。同时发现心肌素在早期心脏形成中的重要性。随着研究的深入，发现心肌素也在血管平滑肌中表达，其中包括主动脉、肺流出道、胃肠及生殖泌尿道的平滑肌。心肌素在胚胎及成年心肌和平滑肌细胞中均有表达，是心肌和平滑肌细胞发育和分化所必需的，本文就今年来有关方面的研究进行综述。     

L-精氨酸对急性心肌梗死大鼠选择素mRNA表达的影响

目的：探讨左旋精氨酸（L-Arg）对急性心肌梗死（AMI）大鼠L、E-选择素mRNA表达的影响及其对心肌的保护作用机制。方法：SD大鼠40只，采用垂体后叶素（Pit）复制急性心肌梗死。设正常组、Pit组、L-Arg治疗组及一氧化氮合酶抑制剂L-NAME组，使用原位杂交检测白细胞L-选择素及心肌微血管内皮细胞E-选择素mRNA的表达，并测定血清TnT、NO₂^-/NO₃^-、CK的浓度以及心肌组织PMNs浸润数。结果：阳性组和L-NAME组，L、E-选择素mRNA表达明显上调（P<0.01或P<0.05），血清NO₂^-/NO₃^-水平显著降低（P<0.01），心肌PMNs浸润数、血清TnT、CK浓度显著增高（P<0.01或P<0.05）。L-Arg组较阳性组，L、E-选择素mRNA表达下调，血清NO₂^-/NO₃^-水平增高（P<0.05），心肌PMNs浸润数、血清TnT、CK浓度降低。结论：外源性L-Arg对AMI大鼠心肌具有保护作用，其作用机制与增加NO合成、抑制选择素mRNA表达有关。     

血管紧张素Ⅱ对动力性肺动脉高压左室心肌细胞凋亡及纤维化的影响

目的观察先天性心脏病（congenital heart disease，CHD）合并肺动脉高压（PAH）患儿心肌细胞凋亡、心肌纤维化及与血浆血管紧张素Ⅱ含量的关系。方法根据有无合并肺动脉高压将20例CHD患儿分为2组，CHD组（n=8）和CHD合并PAH组（n=12），对照组（n=5）为单纯缺血缺氧性脑病患儿。采用TUNEL标记法检测心肌组织中的凋亡细胞，用免疫组化法检测左室心肌细胞Ⅰ型和Ⅲ型胶原蛋白的表达，采用放射免疫法测定血浆血管紧张素Ⅱ浓度。结果CHD组和CHD合并PAH组心肌细胞凋亡指数明显高于对照组，两组左室心肌组织Ⅰ型和Ⅲ型胶原蛋白呈强阳性表达，与对照组相比差异有统计学意义；CHD及CHD合并PAH组血浆AngⅡ水平均显著高于对照组，CHD合并PAH组高于CHD组，且两组相比较有统计学意义。血浆AngⅡ与心肌细胞凋亡指数和Ⅲ型胶原蛋白表达量呈正相关关系，而肺动脉压与心肌细胞凋亡指数和Ⅲ型胶原蛋白表达量及Ⅰ型胶原蛋白表达量无相关关系。结论在CHD患儿左室心肌细胞凋亡和纤维化的过程中，AngⅡ可能比肺动脉压力发挥着更重要的作用，所以应用ACEⅠ阻断肾素-血管紧张素加以降低肺动脉压对提高降低病死率有重要意义。     

心脏糜酶活性改变在心肌肥厚患者心肌纤维化中的意义

目的： 观察心脏糜酶与心肌肥厚患者心肌组织胶原合成和心肌纤维化的关系。方法: 应用病理检查、放射免疫、计算机分析和逆转录-聚合酶链式反应等方法，检测心肌肥厚患者（心肌肥厚组）和正常人（对照组）心脏糜酶活性、心肌局部血管紧张素II（Ang II）水平、心肌胶原容积分数（CVF）、心肌血管周围胶原面积比（PVCA）及心肌组织I型和III型胶原mRNA表达。心脏糜酶活性和心肌局部Ang II水平与CVF及PVCA之间的关系采用相关分析。结果: 心肌肥厚组心脏糜酶活性为(0.27±0.06) kU/g蛋白，对照组为(0.12±0.06) kU/g蛋白，心肌肥厚组心脏糜酶活性明显高于对照组（P<0.01）。心肌肥厚组心肌组织匀浆液Ang II水平为(179.3±36.1) ng/g心肌组织，对照组心肌组织匀浆液Ang II水平为(103.2±13.6) ng/g心肌组织，心肌肥厚组心肌组织Ang II水平明显高于对照组（P<0.01）。心肌肥厚组CVF为39.5%±9.8%，对照组为20.9%±8.2%，心肌肥厚组明显高于对照组（P<0.01）；心肌肥厚组PVCA为1.98±1.05，对照组为0.41±0.12，心肌肥厚组也明显高于对照组（P<0.01）。心肌肥厚患者心肌组织I型胶原及III型胶原mRNA表达相对含量均明显高于正常人（均P<0.01）。心脏糜酶活性与CVF及PVCA呈明显正相关（相关系数分别为0.52和0.69，P<0.05和P<0.01）。心肌局部Ang II水平也与CVF及PVCA呈明显正相关（相关系数分别为0.49和0.58，均P<0.05）。结论: 心脏糜酶可增加胶原的合成，参与细胞外基质的形成和降解，促进心肌纤维化。     

花生四烯酸乙醇胺的心血管作用

花生四烯酸乙醇胺（AEA）是一种内源性大麻素样物质,可与大麻素受体（CBR）和辣椒素受体（TRPV1）结合而发挥广泛复杂的生物学效应。AEA能通过神经调节机制或直接作用于内皮细胞、血管平滑肌、心肌等,在调节心血管系统的生理功能中发挥重要作用。内源性AEA水平的改变与高血压、心肌缺血损伤等多种心血管疾病的发生密切相关。     

急性压力超负荷诱导心肌内分泌活化

目的：探讨压力超负荷致心肌肥大的跨膜信号传递机制。方法：利用放射免疫法及分光光度法动态观察压力超负荷后大鼠心肌组织血管紧张素转换角活性，血管紧张素Ⅱ、内皮索和一氧化氢含量的变化，并观察它们与压力超负荷心肌肥大的关系。结果：随大鼠动脉血压逐步升高，心肌组织中血管紧张素转换酶活性，血管紧张素Ⅱ、内皮素含量均迅速升高（P＜0．05），并持续保持高水平，血管紧张素Ⅱ升高早于内皮系，而一氧化氛含量迅速降低并持续受抑（P＜0．05）。结论：心肌内分泌活化可能是介导压力超负荷致心肌肥大的重要机制。     

伊贝沙坦和培垛普利对左心室肥大时心肌连接蛋白43、结蛋白与肌钙蛋白T表达的实验研究

目的：探讨左室肥大时血管紧张素Ⅱ受体Ⅰ型拮抗剂伊贝沙坦和血管紧张素转换酶抑制剂培垛普利对心肌连接蛋白43（CX43）、结蛋白与肌钙蛋白T（cTnT）表达的影响。 方法： 分假手术组、SD大鼠腹主动脉部分结扎的手术组及腹主动脉部分结扎的处理组即伊贝沙坦组（20 mg·kg-1·d-1 ig）、培垛普利组（2 mg·kg-1·d-1 ig）、两药联用组（伊贝沙坦组20 mg·kg-1·d-1 ig+培垛普利组2 mg·kg-1·d-1 ig），术后次周起干预8周，观察左室重量指数（LVMI）和心肌细胞横径（TDM），免疫组织化学检测心肌CX43、结蛋白与cTnT 表达。 结果： 培垛普利组、伊贝沙坦组和联合用药组LVMI和TDM均显著低于手术组（P<0.05），手术组心肌细胞闰盘区域和侧侧连接的胞膜上均有不规则CX43表达；伊贝沙坦组、培垛普利和其联用组的CX43表达分布较有规律，主要以带状表达于闰盘；手术组心肌CX43、结蛋白、cTnT表达量明显少于伊贝沙坦组、培垛普利组和其联用组（P<0.05）。 结论： 左室肥大时伊贝沙坦和培垛普利有利于心肌CX43、结蛋白与cTnT的表达与分布，能减轻左室心肌肥大，减少心肌细胞损伤，促进心肌细胞骨架结构与缝隙连接的基本正常恢复。     

加味镇眩颗粒对高血压大鼠心肌基质金属蛋白酶-2和微血管密度的影响

目的观察加昧镇眩颗粒对自发性高血压大鼠（SHR）血浆血管紧张素Ⅱ（AngⅡ）、心肌基质金属蛋白酶-2（MMP-2）表达水平和微血管密度（MVD）的影响。方法将50只SHR大鼠随机分为加味镇眩颗粒高剂量组、加味镇眩颗粒中剂量组、加味镇眩颗粒低剂量组、卡托普利组、SHR对照组,经过12周的干预,分别测定动物血压变化,血浆AngⅡ含量、免疫组织化学法检测心肌MMP-2蛋白表达水平、心肌微血管密度。结果治疗组均可降低SHR血压、血浆AngⅡ含量、心肌MMP-2蛋白表达水平,增加SHR心肌微血管密度,与SHR组相比差异具有统计学意义（P〈0．05）,中药组中,加味镇眩颗粒高剂量组效果最好。与卡托普利组相比,高剂量组在12周末降压效果相当（P〉0．05）,且更能降低心肌MMP-2蛋白表达水平（P〈0．05）,增加SHR心肌微血管密度（P〈0．05）。结论加味镇眩颗粒可降低SHR血压,可能与降低血浆血管紧张素Ⅱ含量．下调心肌MMP-2蛋白表达水平,改善SHR大鼠心肌微血管稀疏的作用有关。     

Thrombotic tendency and laboratory medicine in metabolic syndrome

Metabolic syndrome is defined as a complex of hypertriglyceride, insulin resistance, hypertension, and accumulation of visceral fat. This syndrome is often accompanied by thrombotic diseases (e.g., myocardial infarction, cerebral infarction), but the mechanism (s) of thrombotic tendency has not yet been elucidated. Plasminogen activator inhibitor-1 (PAI-1), a principal regulator of fibrinolytic system, plays a pathological role in the development of thrombosis and cardiovascular diseases. PAI-1 is regarded to be one of adipocytokines because it is produced and secreted by adipocytes. The expression of PAI-1 in adipocytes is upregulated by insulin, TNF-alpha, and TGF-beta, suggesting that it is relevant to insulin resistance. PAI-1 antigen level in plasma is elevated in obese subjects and increases in parallel with their BMI and visceral fat. It was experimentally revealed that PAI-1 expression in adipose tissue was dramatically increased in genetically obese mice and abundant expression of PAI-1 was localized to adipocytes in vivo. PAI-1 deficient mice were resistant to high fat diet-induced body weight gain, adipose accumulation, and insulin resistance in association with lack of decreased expression of adiponectin. Taken together, PAI-1 may be a key molecule to develop obesity and insulin resistance as well as thrombotic diseases. It is possible to prevent thrombotic complications and cardiovascular diseases in obese patients by controlling PAI-1 expression and function. Each pathology included in metabolic syndrome could stimulate PAI-1 expression, and thus, PAI-1 would be a good marker of progression of metabolic syndrome itself and of risk for thrombotic cardiovascular diseases as well.     

血管紧张素转换酶2与心血管疾病研究进展

血管紧张素转换酶2(ACE2)是SARS病毒(SARS-CoV)、新型冠状病毒(SARS-CoV-2)感染机体的主要受体,也是肾素-血管紧张素-醛固酮系统的主要成员之一。ACE2对多种心血管疾病具有保护作用,SARS-CoV-2可以降低机体ACE2的表达,这可能是新型冠状病毒肺炎(COVID-19)后期产生心血管并发症的原因之一。本文总结了ACE2在多种心血管疾病发病过程中的作用及其机制,希望为新型冠状病毒肺炎(COVID-19)的治疗提供新的思路。     

Neuroendocrine and Behavioral Mechanisms Mediating the Relationship between Anger Expression and Cardiovascular Risk: Assessment Considerations and Improvements

The hypothesis that intense anger experience may increase risk for or exacerbate cardiovascular diseases has been under active theoretical and empirical interest for decades. Biopsychological models of disease suggest that persons displaying exaggerated physiological responses to acute emotional or stressful states are at a greater risk to develop cardiovascular disorders. The last two decades have witnessed active work to refine means by which anger expression can be assessed, and laboratory research has produced evidence suggesting that certain expression styles may predict enhanced physiological responses to acute stress. In this paper, we review methodological and definition issues related to the assessment of anger, and we summarize recent improvements on the assessment of anger expression. We also review recent studies addressing the association between anger and cardiovascular diseases, and we present potential neuroendocrine and behavioral mechanisms through which anger expression may increase risk for cardiovascular disease.     

Nogo在心脏中的分布及其在心血管疾病中的作用

Nogo作为网状蛋白家族成员,主要参与组织损伤后再生、细胞凋亡和肿瘤生长等过程.心血管疾病是目前威胁人类健康的主要疾病之一.近年来关于Nogo在心血管系统的研究愈加广泛,在心肌纤维化、心肌细胞凋亡和血管重塑等病理过程中Nogo表达的变化提示其可能发挥一定的作用.本文中我们就Nogo在心脏中的分布及心血管疾病中作用作一综...     

蛋白质组学在心血管研究中的应用

随着基因组数据库的不断完善和蛋白质组学技术的不断发展，已有越来越多的研究者将蛋白质组学运用到心血管疾病研究中，即运用2—DE、质谱等手段来观察心肌缺血、高血压、心肌肥大、心衰、心肌梗塞导致的心肌细胞蛋白质表达水平和翻译后修饰(PTM)的改变，对这些急慢性心血管疾病的分子机制给予独特的解释。与此同时，各种心血管疾病模型相关蛋白质组数据库也在建设之中，这将大大方便更多的蛋白质组研究。本文综述了近年来使用蛋白质组学在心血管研究中所取得的进展。     

微小RNAs与心血管疾病

微小RNA (miRNA)是一类内源性的单链非编码小RNA(长度约16 ～ 25个核苷酸).它们通过与靶信使RNA的3′UTR碱基互补配对,形成RNA诱导沉默复合体(RNA-induced silencing complex,RISC),抑制蛋白质的翻译或促进信使RNA分解,从而对靶基因的表达起着反向调节作用.MiRN...     

Homocysteine, hRIP3 and congenital cardiovascular malformations

Elevated serum homocysteine (Hcys) levels have been suggested to contribute to congenital cardiovascular malformations, neural tube defects, and cardiovascular diseases. To investigate the mechanisms resulting in cardiovascular diseases and birth defects, Kuang-Hueih Chen et al. identified and characterized a novel gene, named rHCY2, whose expression was markedly up-regulated when Hcys was elevated in rat. In vivo, rHCY2 gene could induce chicken embryonic cells apoptosis and embryonic malformations. Its N-terminal kinase domain is apparently similar to human receptor-interacting serine–threonine kinase 3 (hRIP3). In view of this, we hypothesize that a link between the teratogenic effects of Hcys and hRIP3 is theoretically plausible. However, given the lack of data on the topic, it remains to be seen whether an elevated serum Hcys level will increase the expression of hRIP3. Using normal and abnormal human fetal hearts and cultured normal human fetal cardiomyocytes, we show that congenital cardiovascular malformations are associated with the overexpression of hRIP3, and evidence is found for a certain association between overexpression of hRIP3 and homocysteine-induced congenital cardiovascular malformations. Folic acid and anti-hRIP3 antibodies seem to favor maintenance of the shape and ultrastructure of cultured human fetal cardiomyocytes. Lijun Zhao and Guangming Wang contributed equally to this work.     

MicroRNA Microarray Expression Profiling in Human Myocardial Infarction

MicroRNAs (miRNAs), small non-coding RNA molecules, are negative regulators of gene expression. Recent studies have indicated their role in various forms of cardiovascular disease. In spite of the number of miRNA microarray analyses performed, little is known about the genome-wide miRNA expression pattern in human myocardial infarction (MI). Using miRNA microarrays and bioinformatic analysis, miRNA expression was analyzed on human MI and foetal hearts compared to healthy adult hearts, to determine whether there is any similar expression pattern between MI and foetal hearts, and to identified miRNAs that have not previously been described as dysregulated in cardiovascular diseases. Of 719 miRNAs analyzed, ∼ 50% were expressed in human hearts, 77 miRNAs were absent from all tested tissues and 57 were confidently dysregulated in at least one tested group. Some expression patterns appeared to be similar in MI and foetal hearts. Bioinformatic analysis revealed 10 miRNAs as dysregulated in MI not yet related to cardiovascular disease, and 5 miRNAs previously described only in animal models of cardiovascular diseases. Finally, qRT-PCR analysis confirmed dysregulation of 7 miRNAs, miR-150, miR-186, miR-210, miR-451, and muscle-specific, miR-1 and miR-133a/b; all of these are believed to be involved in various physiological and pathological processes.     

Circulating microRNAs: novel biomarkers for cardiovascular diseases

MicroRNAs (miRNAs) are a novel class of small, non-coding, single-stranded RNAs that negatively regulate gene expression via translational inhibition or mRNA degradation followed by protein synthesis repression. Many miRNAs are expressed in a tissue- and/or cell-specific manner and their expression patterns are reflective of underlying patho-physiologic processes. miRNAs can be detected in serum or in plasma in a remarkably stable form, making them attractive biomarkers for human diseases. This review describes the progress of identifying circulating miRNAs as novel biomarkers for diverse cardiovascular diseases, including acute myocardial infarction, heart failure, coronary artery disease, diabetes, stroke, essential hypertension, and acute pulmonary embolism. In addition, the origin and function and the different strategies to identify circulating miRNAs as novel biomarkers for cardiovascular diseases are also discussed. Rarely has an opportunity arisen to advance such new biology for the diagnosis of cardiac diseases.