The direct effect of statins on cardiovascular function

心血管疾病（CVD）是西方世界的主要死亡原因。心血管疾病的发病率和患病率在老年人中最高，这是由于年龄增长对心脏和血管的有害影响1。他汀类药物是一类抑制酶HMG-CoA还原酶的药物，其导致肝脏中胆固醇生物合成减少和血浆LDL-胆固醇水平降低，最终减少患者的动脉粥样硬化。除了对肝脏中胆固醇的影响外，他汀类药物还对心血管功能具有积极的多效性作用。先前的研究表明，他汀类药物是心脏内皮细胞中ERK 5激酶的有效激活剂，可调节紧密连接形成和血管通透性2，以及心肌细胞中ERK 5激酶的有效激活剂，可改善线粒体功能。我们的假设是，他汀类药物激活心肌细胞和心脏内皮细胞中的ERK 5，改善心脏功能，并最终防止心脏病变，如衰老。这项研究可能会影响人类心血管衰老的长期管理。我们已经开发了一种新的体外人多细胞心脏微组织，适合长期研究心血管功能3。该项目将利用该模型分析他汀类药物对心脏微组织的长期影响，分析收缩性（微电极阵列）等功能参数和细胞结构（蔡司光片显微镜）等结构参数。通过比较一系列不同的他汀类药物，我们将确定最具心脏选择性的他汀类药物和有效的给药方案，以进行动物研究。第二个目的是使用C57 B1/6小鼠模型来分析他汀类药物治疗后的心脏和血管性能。将通过心脏磁共振成像（MRI）监测心血管生理学。将使用免疫荧光和透射电子显微镜（TEM）对固定的心脏组织进行结构分析。

Cardiovascular disease (CVD) is the leading cause of death in the western world. The incidence and prevalence of CVD is highest among the elderly due to the deleterious effects of advancing age on the heart and blood vessels1. Statins are a class of drugs which inhibit the enzyme HMG-CoA reductase leading to reduced cholesterol biosynthesis in the liver and a lowering of plasma LDL-cholesterol levels, ultimately reducing atherosclerosis in patients. In addition to their effects on cholesterol in the liver, statins are known to have positive pleiotropic effects on cardiovascular function. Previous work has shown that statins are potent activators of ERK5 kinase in cardiac endothelial cells, which regulates tight junction formation and vascular permeability2 and in cardiomyocytes, which may lead to improved mitochondrial function. Our hypothesis is that statin activation of ERK5 in both cardiomyocytes and cardiac endothelial cells improves cardiac function and ultimately protects against cardiac pathologies such as aging. This research could impact on the long-term management of cardiovascular aging in humans. We have developed a novel in vitro human multicellular cardiac microtissue amenable to long-term studies of cardiovascular function3. The project will utilise this model to analyse the long-term effect of statins on cardiac microtissue analysing functional parameters such as contractility (microelectrode array) and structural parameters such as cellular architecture (Zeiss light sheet microscopy). By comparing a range of different statins we will identify the most cardioselective statin and efficient dosing regimen to progress to an animal study. The second aim will be to use a C57Bl/6 mouse model to analyse cardiac and vascular performance following statin treatment. Cardiovascular physiology will be monitored by cardiac magnetic resonance imaging (MRI). Structural analysis on fixed cardiac tissue will be perform by using immunofluorescence and transmission electron microscopy (TEM).