应用光遗传学技术调控超负荷引起的心脏重塑及其力学行为

Myocardial fibrosis and myocardial hypertrophy is characterized mainly by cardiac cells becoming hypertrophy and the components of cardiac extracellular matrix (ECM) changing, that is cardiac remodeling, which are the results of self-adaptation response to the heart overloading. The direct effect of myocardial fibrosis and hypertrophy on the cardiac function is the increasing incidence rate of heart failure and arrhythmia, decreasing of coronary flow reserve, and adding myocardial ischemic events. Thus, myocardial fibrosis and myocardial hypertrophy is independent and dangerous factor that induce significant increasing of the incidence of cardiovascular disease and mortality rate. Optogenetics has emerged as an new method for controlling cellular transmembrane potential. The objective of this project is to express light sensitive ion channel in cardiomyocytes and myofibroblasts , then we utilize optical stimulation methods to regulate cellular membrane potential and analyze, at the cellular and animal level, the effects of membrane potential controllability on the cardiac remodeling of heart and cardiac fibroblasts under mechanical overloading. We apply this framework to explore the critical role of two types important enzymes in the process of cardiac remodeling. We investigate the effect of matrix metalloproteinases (MMPs) and its physiological inhibitor tissue inhibitors of metalloproteinases (TIMPs) on the ECM remodeling during myocardial hypertrophy in rats, and its effect of intervention of optogenetic. Additionally, we utilize hemodynamics method to evaluate the influence of intervention of optogenetic on the Cardiac function and mechanical behavior in myocardial hypertrophy. This project would certainly pave the way to gaining a new insight into the pathogenesis of cardiovascular diseases, at the same time, this project also provide experimental evidences for applying photo-stimulation to treat cardiovascular diseases.

心肌肥厚和纤维化是心肌对超负荷产生自我适应的结果，主要表现为心肌细胞肥大和细胞外基质成分的改变，即心脏重建（remodeling）。其对心脏的直接作用是增加心衰和心律失常的发生率，减少冠状动脉血流储备，增加心肌缺血事件。因此，是引起心血管疾病发生率和死亡率显著升高的独立危险因素。光遗传学（optogenetics）调控是近几年发展起来可控制细胞跨膜电位的新技术。本项目拟应用光遗传学技术将光敏感离子通道表达于心肌细胞与心肌成纤维细胞，以光刺激的办法来调控细胞膜电位。进而在细胞和动物水平上分析膜电位调控对心脏、心肌细胞、心肌成纤维细胞在力学超载时重塑的影响。探讨在心脏重塑中起关键作用的酶：金属基质蛋白酶(MMPs)及其生理性抑制剂TIMPs在心肌肥厚大鼠细胞外基质重塑中的作用及光遗传学干预的效果。应用血流动力学分析方法评价光遗传学干预对心肌肥厚心脏功能及力学行为的影响。

心肌肥厚和纤维化是心肌对超负荷产生自我适应的结果，主要表现为心肌细胞肥大和细胞外基质成分的改变，即心脏重建（remodeling）。其对心脏的直接作用是增加心衰和心律失常的发生率，减少冠状动脉血流储备，增加心肌缺血事件。因此，是引起心血管疾病发生率和死亡率显著升高的独立危险因素。光遗传学（optogenetics）调控是近几年发展起来可控制细胞跨膜电位的新技术。本项目成功的将光敏感离子通道表达于心肌细胞与心肌成纤维细胞并可应用光诱导产生跨膜电流，实现了通过光刺激的办法来调控心肌细胞膜电位。研究发现心脏重塑中起关键作用的酶：金属基质蛋白酶(MMPs)及其生理性抑制剂 TIMPs 的活性被光刺激改变。光刺激可以降低表达有光敏感阴离子通道的心肌细胞膜电位进而影响动作电位的发放。研究证实了BK通道可以通过减弱L-型钙通道的功能而降低心肌细胞钙浓度。随着基底刚度的增加BK通道的表达和功能均降低，从而减弱了对胞内钙浓度调控的能力。这些研究将对应用物理干预的手段治疗心血管疾病提供重要的参考。