他汀类药物的非调脂机制研究进展

他汀类药物非调脂作用包括改善内皮功能、抑制血栓形成、减轻氧化应激和炎症反应、抑制血管平滑肌细胞增殖、抑制心肌肥厚、增加外周血内皮祖细胞，在心血管疾病的治疗中具有重要价值。     

性腺机能减退患者进行睾酮治疗前后伐地那非对内皮祖细胞水平的影响

目的通过分析睾酮治疗前后伐地那非对性腺机能减退患者内皮祖细胞的作用评价磷酸二酯酶5抑制剂和睾酮治疗对内皮祖细胞作用的关系。方法治疗组为15名性腺机能减退的患者,对照组为25名年龄相当、性腺机能正常的志愿者。测定患者睾酮治疗前和睾酮治疗6个月后给予伐地那非前后患者体内循环内皮祖细胞和祖细胞的水平变化。结果和对照组相比,睾酮治疗前治疗组患者内皮祖细胞和祖细胞水平显著低于对照组,并且睾酮治疗前服用伐地那非对性腺机能减退患者的内皮祖细胞和祖细胞水平均没有显著影响。经过6个月的睾酮治疗后性腺机能减退患者性腺功能增强,内皮祖细胞和祖细胞水平显著增加,并且达到正常组的水平。经过治疗后,伐地那非显著增加性腺机能减退患者内皮祖细胞和祖细胞的水平,作用和对照组相似。结论睾酮治疗后伐地那非可增加性腺机能减退患者的内皮祖细胞水平,并且体内正常的睾酮水平是维持内皮祖细胞对磷酸二酯酶5抑制剂应答的必需条件。     

阿托伐他汀对2型糖尿病患者外周血内皮祖细胞功能的影响及其机制的初步探讨

目的观察阿托伐他汀对2型糖尿病患者(T2DM)患者外周血内皮祖细胞功能的影响并初步探讨其机制。方法将40例糖尿病患者随机分为他汀治疗组和对照组,前者给予阿托伐他汀40 mg/d口服,治疗前及治疗后2、4周抽取外周血,采用密度梯度离心法分离培养内皮祖细胞,应用噻唑蓝(MTT)法检测内皮祖细胞增殖情况,Transwell小室检测迁移,Matrigel管腔形成实验检测管腔形成能力。另取20例T2DM患者血培养内皮祖细胞,加入阿托伐他汀、一氧化氮合酶(NOS)/NO途径抑制剂L-NAME后观察对其功能的影响。结果阿托伐他汀治疗后2周、4周外周血内皮祖细胞数量明显上升,功能明显改善(P<0.01)。体外实验他汀+L-NAME组的血内皮祖细胞数目较他汀组明显下降(P<0.01)。结论阿托伐他汀对糖尿病患者内皮祖细胞的功能具有一定保护作用,这种作用能被L-NAME阻断。阿托伐他汀的作用机制可能与激活NOS/NO信号通路有关。     

糖尿病患者血管内皮祖细胞研究进展

血管内皮祖细胞(EPC)来源于骨髓,是具有修复内皮和新生血管功能的干细胞。糖尿病患者外周血EPC数量和功能均出现下降,EPC已成为糖尿病及其并发症治疗的一个新靶点。本文综述EPC在糖尿病病理生理中的作用和药物干预机理的研究进展。     

内皮祖细胞与高血压的关系

内皮祖细胞EPCs（Endothelial progenitor cell）是内皮细胞的前体细胞,近年来的研究表明EPCs和心血管疾病的关系密切,现对EPCs与高血压相互关系以及未来的前景方面予以综述。     

血滞通胶囊对缺血性心脏病患者血管内皮功能的影响

许多心血管疾病的高危因素均可导致血管内皮功能损伤,而血管内皮功能损伤又常伴发或加重心血管疾病。因此保护血管内皮功能,改善血管内皮功能障碍已成为治疗心血管疾病的重要策略之一。我们在用血滞通胶囊治疗缺血性心脏病的过程中通过高分辨超声技术对患者血管内皮舒张功能进行检测,发现血滞通胶囊具有明显的改善缺血性心脏病患者的血管内皮功能的作用。现报告如下。     

葛根素对血管内皮功能的作用

血管内皮与多种心血管疾病的发生密切相关,寻找改善血管内皮功能障碍的药物具有重要意义。葛根素在保护血管内皮上具有重要作用,能扩张微血管,改善微循环,抗血小板聚集等。本文对其改善血管内皮功能作一概述。     

盐酸小檗碱的心血管药理活性研究进展

小檗碱是一种异喹啉生物碱,存在于黄连、黄檗等植物中,临床常用其盐酸盐.盐酸小檗碱具有强心、抗心律失常、内皮保护、心肌保护、降压、抗动脉粥样硬化、糖尿病性心血管疾病治疗等心血管药理活性作用,是一种富有潜力的心血管疾病治疗药物.本文通过对PubMed数据库进行检索,对盐酸小檗碱的心血管药活性研究进行了综述.     

瓜蒌皮治疗心血管疾病的作用机制及临床应用概况

目的:总结瓜蒌皮治疗心血管疾病的作用机制及临床应用概况,为拓展瓜蒌皮的临床应用提供参考。方法:以"瓜蒌皮""心血管""药理作用""机制""临床应用""Gualoupi""Cardiovascular""Pharmacology""Mechanisms""Clinical research"等为关键词,组合查询2007年1月-2019年5月中国知网、万方数据、维普网、Pub Med、Google学术等数据库中的相关文献,对瓜蒌皮治疗心血管疾病的作用机制和临床应用进行归纳总结。结果与结论:共检索到相关文献189篇,其中有效文献63篇。瓜蒌皮可通过保护血管内皮细胞、抑制血栓形成、增强内皮祖细胞功能、抗肾素及血管紧张素、抗炎、抑制血管平滑肌增殖、稳定动脉粥样硬化等作用机制发挥治疗心血管疾病的作用。临床应用中发现,瓜蒌皮在治疗缺血性脑卒中、改善经皮冠状动脉介入治疗(PCI)术后患者生活质量和治疗心力衰竭、心肌梗死、心绞痛等方面疗效显著。瓜蒌皮成分复杂,其治疗心血管疾病的作用机制可能是多种活性成分共同作用的结果,建议开展更多的研究以进一步明确其活性成分在治疗心血管疾病方面的作用机制,拓展瓜蒌皮的临床应用,为其后续开发提供参考。     

参麻颈复方对脑缺血损伤小鼠的脑保护作用及其机制研究

目的 观察参麻颈复方颗粒对脑缺血损伤小鼠脑组织的保护作用，并探讨其可能机制。方法 将SPF级C57 BL/6雄性小鼠30只随机分为模型对照组、参麻颈组、尼莫地平组，采用电凝法制备小鼠脑缺血损伤动物模型，给参麻颈组、尼莫地平组小鼠灌胃14 d，应用TTC染色法检测各组小鼠脑梗死体积，提取骨髓内皮祖细胞并测定细胞功能，用蛋白免疫印迹法（Western blot）检测内皮祖细胞中蛋白表达水平。结果 与模型对照组比较,参麻颈组小鼠脑梗死体积明显减少，其内皮祖细胞迁移、黏附以及形成小管的能力显著改善，内皮祖细胞中BDNF蛋白表达水平明显升高。结论 参麻颈复方颗粒对脑缺血损伤小鼠脑组织具有保护作用，可能与调节内皮祖细胞中BDNF的表达，改善骨髓来源内皮祖细胞功能密切相关。     

Endothelial progenitors in vascular repair and angiogenesis: how many are needed and what to do?

Defects in the regulation of neo blood vessel growth (angiogenesis) or in vessel repair are major complications in many diseases, such as cancer, diabetes, atherosclerosis and myocardial infarction. In these diseases it was shown that the number of circulating endothelial progenitor cells (EPC) was altered. This has been associated with the angiogenic status and patient prognosis. However, the regulation of angiogenesis depends not only on the number of circulating EPC but also on their functions. EPC are bone marrow derived cells that are recruited into the peripheral blood in situations of vascular repair/angiogenesis or vascular stress. EPC are believed to exert their function using mainly two strategies: activating locally the endothelial cells and/or differentiating into mature endothelial cells that integrate the damaged vessels. To do this, EPC must home to "angiogenic active" sites, adhere to the activated/damaged endothelial cells or to the extracellular matrix and participate in the endothelial activation/repair process. In vitro and in vivo experiments using animal models revealed the importance of various signalling pathways in these processes and, in patients, new therapeutic strategies are being developed based on the specific functions of EPC. Although the role of EPC in vessel repair in disease is not totally understood, it becomes clear that the activation state of these cells is critical for the vessel repair process. Our previous work generated a detailed gene expression profile of EPC during the endothelial differentiation process in vitro. With this information, it has been possible to identify numerous molecular targets crucial for EPC differentiation and function and to test their involvement in EPC function during wound healing or tumor angiogenesis. The importance of EPC identification, activation state and function in vascular repair and in angiogenesis in disease will be discussed in this review.     

The role of endothelial progenitor cells and statins in endothelial function: a review

Endothelial dysfunction, a well recognized marker of cardiovascular risk, is an early event in arteriosclerosis process. Diabetes mellitus, hypertension and dyslipidemia, known risk factors for coronary disease have been associated with endothelial dysfunction, which improves after the control of these factors. Statins have additional benefits on endothelial function not related to decreasing cholesterol levels, known as pleiotropic effects. Most recently it has been reported the effect of statins promoting bone marrow-derived mononuclear cells. These cells are positive for CD34 and KDR superficial markers of endothelial cellular lineage, which is consistent with the hypothesis that they constitute the endothelial progenitor cells. Circulating endothelial progenitor cells are involved in the repair process of the endothelium after endothelial-cell injury in myocardial ischemia, angina and other stressful situations. Recent studies have demonstrated an inverse relationship between the EPC count in peripheral blood and risk of developing a cardiovascular event. In addition, circulating EPC correlates with the presence of endothelial dysfunction and could play a role as a surrogate biologic marker in vascular function. The effect of statins on endothelial progenitor cells might contribute to improve endothelial function leading to a decrease in vascular risk, independently of their impact on LDL cholesterol. In this paper, we review the role of statins in EPC mobilization, its effect in endothelial function restoration and the relevance of this finding in cardiovascular risk. We also review future therapeutic implications.     

Oxidative stress on progenitor and stem cells in cardiovascular diseases

There is accumulating evidence that reactive oxygen species (ROS) play major roles in the initiation and progression of cardiovascular dysfunction associated with diseases such as hyperlipidemia, diabetes mellitus, hypertension, ischemic heart disease, and chronic heart failure. ROS produced by migrating inflammatory cells as well as vascular cells (endothelial cells, vascular smooth muscle cells, and adventitial fibroblasts) have distinct functional effects on each cell type. These effects include cell growth, apoptosis, migration, inflammatory gene expression and matrix regulation. ROS, through regulating vascular cell function, can play a central role in normal vascular physiology, and contribute substantially to the development of cardiovascular diseases. Excessive production of ROS is an essential mechanism underlying the pathogenesis of endothelial dysfunction and cardiovascular disease. Stem cells hold great promise for tissue repair and regenerative medicine, and endothelial progenitor cells (EPC) play a significant role in neovascularization of ischemic tissue. Recent studies have shown that cardiovascular risk factors such as hypertension, hypercholesterolemia, diabetes and cigarette smoking are inversely correlated with EPC number and function. Understanding the mechanisms, that regulate EPC function may provide new insights into the pathogenesis of vasculogenesis and may promote development of specific therapies to prevent ROS production and ultimately correct EPC dysfunction. We have demonstrated the angiotensin II receptor blockers improve EPC dysfunction through antioxidative mechanisms. In the present review, we describe our current understanding of the contributions of oxidative stress to progenitor and stem cell dysfunction in cardiovascular disease and focus on the potential mechanisms that underlie oxidative stress-induced damage of progenitor and stem cells.     

改善糖尿病内皮祖细胞功能的研究进展

内皮祖细胞（EPC）为来源于骨髓及外周血中的干细胞,能定向增殖分化为内皮细胞,参与血管损伤后的修复。研究显示,改善糖尿病EPC功能,可以预防和降低糖尿病并发症的发生。追踪近年来改善EPC功能的研究进展,就其对糖尿病并发症的预防和改善作用做一综述,以期为糖尿病的治疗提供新思路。     

Circulating endothelial progenitor cells as biomarkers for prediction of cardiovascular outcomes

Experimental studies suggest that bone marrow-derived endothelial progenitor cells (EPCs) play an important role in the maintenance of endothelial integrity and hemostasis. The number of circulating EPC has been shown to be inversely correlated with cardiovascular risk factors and vascular function and to predict cardiovascular events independent of both traditional and non-traditional risk factors. Thus, EPCs provide a clinical advantage over the use of other biomarkers as their measurement is directly associated with endothelial function, and available evidence suggests that they are consistently and significantly associated with a spectrum of cardiovascular complications, such as acute coronary syndromes and coronary artery disease. However, many issues in the field of EPC isolation and identification, particularly in regards to the effective and unequivocal molecular characterization of these cells still remain unresolved. In addition, simple EPC counts do not adequately describe cardiovascular disease risk. This limitation is attributable to variation in the definition of EPCs, the number of existing cardiovascular risk factors in different patients as well as a difference in the interaction between EPCs and other hematopoietic progenitor, inflammatory cells or platelets.     

The effects of HMG-CoA reductase inhibitor on vascular progenitor cells

Circulating bone marrow-derived vascular progenitor cells contribute to angiogenesis, atherosclerosis, and the response to vascular injury. These vascular progenitor cells consist of two cell groups, endothelial progenitor cells (EPCs) and smooth muscle progenitor cells (SMPCs). Although HMG-CoA reductase inhibitors (statins) have been reported to inhibit atherosclerosis partially by increased EPCs, the effects of statins on SMPCs are unclear. Therefore, we investigated the relationship between EPCs and SMPCs and whether pravastatin has atheroprotective effects on SMPCs. Peripheral mononuclear cells (MNCs) were isolated and cultured on fibronectin-coated dishes in SMPC medium. MNCs were stained with acetylated low density lipoprotein and lectin, or alpha-smooth muscle actin, and cell numbers were counted. mRNA expression and vascular endothelial growth factor (VEGF) protein synthesis of MNCs were evaluated. Pravastatin significantly increased the number of EPC and decreased the number of SMPC. mRNA expression of VEGF, endothelial nitric oxide synthase, VEGF receptor-2 (KDR), and Akt were up-regulated, and VEGF secretion was increased by pravastatin. The present study demonstrated that pravastatin has promotive effects on the differentiation from MNCs to EPC cells, while inhibitory effects to SMPC cells. Our findings suggest a previously unreported mechanism of the effect of statin therapy on vascular progenitor cells.     

The pleiotropic effects of ARB in vascular endothelial progenitor cells

Angiotensin II regulates blood pressure and contributes to endothelial dysfunction and the progression of atherosclerosis. Bone marrow-derived endothelial progenitor cells (EPCs) in peripheral blood contribute to postnatal vessel repair and neovascularization. Impaired EPC function in patients with hypertension and diabetes inhibits the endogenous repair of vascular lesions and leads to the progression of atherosclerosis. The number of EPCs in peripheral blood is inversely correlated with mortality and the occurrence of cardiovascular events. Angiotensin II-mediated signaling is implicated in oxidative stress, inflammation and insulin resistance, factors that cause EPC dysfunction. Blockade of the angiotensin II type 1 receptor may therefore present a new therapeutic target for enhancing EPC function.     

Endothelial progenitor cells as potential drug targets

Endothelial progenitor cells (EPC) are bone marrow derived cells with the potential to differentiate into mature functional endothelial cells. First clinical trials have been performed investigating the effects of EPC transplantation into cardiac ischemic areas after myocardial infarction, in patients with peripheral atherovascular disease or on endothelialisation of artificial heart valves. Next to EPC transplantation, the pharmacological mobilisation and functional modification of EPC may also play a major role in future therapies. Studies have raised the concern that patients with coronary heart disease or severe heart failure may suffer from decreased amounts and impaired function of peripheral circulating EPC. Drug induced mobilization of EPC and normalization of EPC function may therefore improve prognosis of certain cardiovascular diseases. The underlying molecular events of a disturbed mobilisation, differentiation, homing and/or function of EPC are not well understood. In the present review we will highlight the current knowledge of the role of EPC dysfunction in various cardiovascular diseases and focus on potential causally related molecular mechanisms, which might be novel drug targets.     

Hypoxia inducible factor-1 alpha, endothelial progenitor cells, monocytes, cardiovascular risk, wound healing, cobalt and hydralazine: a unifying hypothesis

Bone marrow-derived mononuclear cells differentiate into endothelial cells in adult animals, including humans. These cells, endothelial progenitor cells (EPCs), play central roles in neovascularization in a variety of physiological and pathological processes. EPCs numbers are clinically relevant; in patients with vascular disease, EPC numbers are predictive of hard clinical endpoints and correlate with vascular health in patients without manifest atherosclerosis. EPCs express CXCR4 which allows homing to sites of neovascularization. The homing signal released by the target tissues is SDF-1 which is the ligand for CXCR4. With release of SDF-1 and reversal of the marrow/periphery gradient, EPCs are mobilized to the periphery where they are recruited to SDF-1 expressing tissues. The SDF-1/CXCR4 axis is the final common pathway for EPC mobilization by hypoxia, angiogenic peptides and G-CSF. Expression of SDF-1 in target tissues and CXCR4 in EPCs as well as angiogenic cytokines such as VEGF are regulated by hypoxia inducible factor-1 alpha (HIF-1 alpha). This paper discusses evidence suggesting that depressed HIF-1 alpha-mediated gene programming is the most fundamental of all cardiovascular risk factors and discusses the manipulation of this system with existing drugs such as cobalt or hydralazine. By stabilizing HIF-1 alpha protein, these compounds will enhance EPC mobilization and function, thereby improving cardiovascular health overall. This paper discusses why previous studies with EPC transplantation or mobilization with G-CSF have had negative results and proposes the use of Cobalt and Hydralazine to enhance EPC function to overcome the dysfunctional EPC phenotype that is seen in patients with vascular disease or cardiovascular risk factors.     

Influence of statin use on endothelial function: from bench to clinics

Endothelial dysfunction has been shown to be a prognostic factor for cardiovascular disease and improvement of endothelial dysfunction prevents cardiovascular event presentation. Endothelial dysfunction is associated to a reduced nitric oxide (NO) bioactivity, as a result of the impairment of NO synthesis/release by the endothelial NO synthase (eNOS) or by inactivation of NO. Endothelial dysfunction measurements are valuable surrogate markers to assess the effectiveness of interventions addressed to prevent or treat coronary heart disease (CHD). Dyslipemia and other cardiovascular risk factors promote endothelial dysfunction and life style changes and pharmacological treatment, particularly HMG-CoA reductase inhibitors (statins), have shown early improve of endothelial-dependent vasomotion. Statins efficiently reduce plasma LDL cholesterol, an effect that may account for their beneficial effect on endothelial function, but they also reduce cellular levels of isoprenoid compounds relevant for the bioavailability of NO. Statins restore NO production by several mechanisms, including up-regulation of eNOS mRNA and protein levels and preservation of NO inactivation by reactive oxygen species (ROS). These effects are mediated, at least in a part, through mechanisms independent of their lipid lowering effect (pleiotropic effects). In this article we discuss the relevance of endothelium-dependent effects on the early and delayed clinical benefit of statins, as well as the multiple ways by which statins may restore endothelial function acting not only on the endothelium but also on endothelial progenitor cells (EPC), which likely could contribute to both ischemia-induced neovascularization and endothelial regeneration after injury.