Autophagy in Myocardial Recovery and Remission

摘要 治疗干预措施，有利于影响心力衰竭(HF)的不良自然病史，要么缓慢，要么 逆转左心室(LV)重塑。部分心力衰竭患者射血分数降低(HFrEF) 逆转的左心室重构与避免未来的临床心衰事件(“心肌恢复”)有关， 而在大多数患者中，左心室结构/功能的最初稳定之后是 进行性左室重构和不良的临床结果(“心肌缓解”)。因此，尽管复苏 左心室结构和功能的改变与心力衰竭临床病程的稳定以及心力衰竭的逆转有关。 许多方面的HF表型，它与自由从未来的HF事件无关。了解 左心室正常化或部分正常化的代偿性心衰患者的临床和生物学特征 结构和功能，但仍然容易受到血液动力学/神经激素应激的影响，这是一个主要的未满足的问题 在心力衰竭领域的需要。这项研究计划的长期目标是勾勒出 逆行左心室心脏功能不稳定的机制 随着左心功能的恢复而重塑，并开发新的治疗方法来解决这一未满足的问题 临床需要。为了探索“心肌缓解”临床现象的生物学基础，我们有 开发了一种临床相关的“可逆性心力衰竭”临床前模型，该模型结合了中度主动脉 狭窄(TAC)和左前降支远端结扎(MI)是导致HFrEF的主要并发症。 工业化国家。为了“逆转”心力衰竭的表型，TAC MI小鼠的血流动力学被卸载 手术解除主动脉缩窄，使左室结构和功能恢复正常。密切相关的 根据目前的建议，当去带的TAC MI小鼠(“HF-DB”小鼠)暴露于神经激素时 应激时，他们会出现左心室肥厚增加和左心室功能障碍增加，类似于在 HFrEF患者在左心室结构和功能恢复后出现功能不稳定。基于我们的 初步观察到自噬-溶酶体系统在发育和发育过程中调节失调 为了从HF中恢复过来，我们检验了以下三个假设：(1)自噬通量在 HF的发展，尽管流量在血流动力学卸载后相对改善，但流量 仍然“低效”(Aim1)；(2)有效逆转左室重构需要自噬流量(Aim2)； 以及(3)自噬通量不足至少部分是导致功能不稳定的原因 在暴露于神经激素应激的反向LV重塑心脏中发展(目标3)。特定的 AIMS 1-3将提供关于自噬在恢复过程中的潜在作用的明确信息 血流动力学卸载后左室结构和功能的变化以及功能不稳定性 可逆性心衰病理生理学相关模型的逆转左室重构。

ABSTRACT Therapeutic interventions that favorably impact the untoward natural history of heart failure (HF) either slow or reverse left ventricular (LV) remodeling. In some patients with HF with a reduced ejection fraction (HFrEF) reverse LV remodeling is associated with freedom from future clinical HF events (“myocardial recovery”), whereas in the great majority of patients the initial stabilization of LV structure/function is followed by progressive LV remodeling and untoward clinical outcomes (“myocardial remission”). Thus, although recovery of LV structure and function are associated with stabilization of the clinical course of HF, as well as reversal of many aspects of the HF phenotype, it is not associated with freedom from future HF events. Understanding the clinical and biological features of “compensated” HF patients, who have normalized or partially normalized LV structure and function, but remain vulnerable to hemodynamic/neurohormonal stress, represents a major unmet need in the field of heart failure. The long term goal of this research initiative is to delineate the mechanisms responsible for the functional instability of hearts that have undergone reverse LV remodeling with recovery of LV function, and to develop new therapies that will address this unmet clinical need. To explore the biological basis for the clinical phenomenon of “myocardial remission,” we have developed a clinically relevant pre-clinical model of “reversible heart failure” that combines moderate aortic constriction (TAC) and distal LAD ligation (MI), which are the major comorbidities that cause HFrEF in industrialized nations. To “reverse” the HF phenotype, the TAC + MI mice are hemodynamically unloaded by surgically removing the aortic constriction, resulting in the normalization of LV structure and function. Germane to the present proposal, when the de-banded TAC + MI mice (“HF-DB” mice) are exposed to a neurohormone stress, they develop increased LV hypertrophy and increased LV dysfunction, analogous to what is observed in HFrEF patients who develop functional instability following recovery of LV structure and function. Based on our preliminary observations that the autophagy-lysosome system is dysregulated during the development and recovery from HF, we prose to test the following three hypotheses: (1) autophagic flux is impaired during the development of HF and, although flux is relatively improved following hemodynamic unloading, flux remains “inefficient” (Aim1); (2) autophagic flux is required for effective reverse LV remodeling (Aim 2); and (3) insufficient autophagic flux is responsible, at least in part, for the functional instability that develops in reverse LV remodeled hearts that are exposed to neurohormonal stress (Aim 3). Specific Aims 1-3 will provide definitive information with respect to the potential role of autophagy in the recovery of LV structure and LV function following hemodynamic unloading, as well as the functional instability of reverse LV remodeling in a pathophysiologically relevant model of reversible HF.