Extracellular drivers of myocyte stiffening in diastolic heart disease

舒张性心脏病，DHD，是全世界死亡和残疾的主要原因。没有FDA批准 在改善舒张功能障碍的治疗方面，NIH特别强调了合作倡议 基础科学家和临床医生之间的合作，重点是了解舒张压的分子机制， 心衰心脏硬化是舒张功能障碍的标志， 心肌细胞和细胞外基质（ECM）的内在。大多数心力衰竭治疗 旨在靶向心肌细胞，而不是病理重塑的ECM对 心肌细胞和心脏功能具有特别的临床重要性。在本提案中，我们利用 最近开发的心脏准备，以探测DHD ECM的机械性能，并确定 对心肌细胞舒张功能的影响。使用已建立的DHD模型，肥胖的DHF1大鼠， 我们确定心肌硬化依赖于心肌细胞和ECM硬化的程度， 并定量分析高血压和DHD中ECM的结构和成分变化。在 目的2研究DHD ECM对心肌细胞结构和功能的影响。通过成熟 在来自正常、高血压和DHD心脏的脱细胞ECM中，我们确定了心脏干细胞的数量。 DHD ECM对心肌细胞结构和功能的影响。带有定制安装 系统，我们将能够测量心脏类器官的舒张性能，无论是在正常或 DHD ECM。与我们的初步数据一致，我们预计将观察到DHD ECM驱动器 心肌细胞肥大、增强的收缩性和受损的舒张。这些结果表明 DHD ECM可以向心肌细胞发出信号，使其具有舒张性心脏病的特征。

Diastolic heart disease, DHD, is a leading cause of death and disability worldwide. With no FDA approved therapies to improve diastolic dysfunction, the NIH has placed special emphasis on collaborative initiatives between basic scientists and clinicians focusing on understanding the molecular mechanism of diastolic heart failure. Cardiac stiffening is a hallmark of diastolic dysfunction and occurs through mechanisms intrinsic to both cardiomyocytes and extracellular matrix, ECM. With the majority of heart failure therapies designed to target cardiomyocytes and not, the influence of pathologically remodeled ECM on cardiomyocyte and cardiac function is of particular clinical importance. In this proposal we leverage a recently developed cardiac preparation to probe the mechanical properties of the DHD ECM and determine its influence of cardiomyocyte diastolic function. Using an established model of DHD, the obese ZSF1 rat, we determine the degree to which myocardial stiffening depends on cardiomyocyte and ECM stiffening respectively and quantify the structural and compositional changes of ECM in hypertension and DHD. In Aim 2 we determine the influence of DHD ECM on cardiomyocyte structure and function. By maturing cardiac stem cells in decellularized ECM from normal, hypertensive and DHD hearts, we determine the influence of the DHD ECM on cardiomyocyte structure and function. With a custom-adapted mounting system, we will be able to measure diastolic performance of cardiac organoids grown in either normal or DHD ECM. Consistent with our preliminary data, we expect to observe that DHD ECM drives cardiomyocyte hypertrophy, enhanced contractility, and impaired relaxation. These results indicate that the DHD ECM can signal cardiomyocytes to adopt characteristics of diastolic heart disease.