Autophagy in Myocardial Recovery and Remission

自噬在心肌恢复和缓解中的作用

基本信息

批准号：
10664928
负责人：
Abhinav Diwan
金额：
--
依托单位：
ST. LOUIS VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10664928
关键词：
Anatomy Angiotensin II Animal Model Autophagocytosis Biochemical Biological Cell physiology Cells Clinical Compensation Deterioration Developed Countries Development Devices Dilated Cardiomyopathy Disease remission Distal EFRAC Event Experimental Models Exposure to Freedom Future Gene Expression Profiling Gene Expression Regulation Genes Goals Growth Guidelines Heart Heart failure Image Impairment Lead Left Ventricular Dysfunction Left Ventricular Function Left Ventricular Hypertrophy Left Ventricular Remodeling Left ventricular structure Ligation Lysosomes Mechanics Medical Modeling Molecular Mus Myocardial Myocardial Ischemia Natural History Neurohormones Operative Surgical Procedures Organelles Outcome Oxidative Stress Pathologic Patients Pharmaceutical Preparations Phenotype Phenylephrine Pre-Clinical Model Proteins Quality Control Recovery Recurrence Research Role Secondary to Stress System Testing Therapeutic Intervention aorta constriction clinically relevant comorbidity endoplasmic reticulum stress evidence base experience experimental study gain of function hemodynamics improved loss of function mouse model novel therapeutic intervention novel therapeutics tissue injury tissue repair

项目摘要

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.

抽象的治疗干预措施可以缓慢或缓慢地影响心力衰竭（HF）的不良自然史在一些射血分数降低（HFrEF）的心力衰竭患者中逆转左心室（LV）重构。逆向左心室重构与未来临床心力衰竭事件的发生（“心肌恢复”）有关，而在大多数患者中，左心室结构/功能最初稳定后，进行性左心室重构和不良临床结果（“心肌缓解”）因此，尽管恢复。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相关。心力衰竭表型的许多方面，它与未来免受心力衰竭事件的影响无关。左心室正常或部分正常的“代偿性”心力衰竭患者的临床和生物学特征结构和功能，但仍然容易受到血流动力学/神经激素应激的影响，这是一个重大的未满足问题这项研究计划的长期目标是确定心力衰竭领域的需求。导致经历逆向左心室的心脏功能不稳定的机制通过恢复左室功能进行重塑，并开发新疗法来解决这一未满足的问题为了探索“心肌缓解”临床现象的生物学基础，我们进行了研究。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缩窄（TAC）和远端 LAD 结扎（MI），这是导致 HFrEF 的主要合并症为了“逆转” HF 表型，TAC + MI 小鼠的血流动力学被卸载。通过手术切除主动脉缩窄，使左心室结构和功能正常化。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和左心室功能障碍增加，类似于在根据我们的研究，在左心室结构和功能恢复后出现功能不稳定的 HFrEF 患者。初步观察自噬-溶酶体系统在发育和发育过程中失调在从 HF 恢复过程中，我们试图检验以下三个假设：（1）自噬流在 HF 恢复过程中受损 HF 的发展，尽管血流动力学卸载后通量相对改善，但通量仍然“低效”（目标 1）；（2）有效的逆向左室重塑需要自噬通量（目标 2）； (3) 自噬通量不足是（至少部分）功能不稳定的原因在暴露于神经激素应激的逆向左心室重构心脏中发生（目标 3）。目标 1-3 将提供有关自噬在恢复中的潜在作用的明确信息血流动力学卸载后左室结构和左室功能的变化以及功能不稳定在可逆性心力衰竭的病理生理学相关模型中进行逆向左心室重塑。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The Programmed Death-1 Signaling Axis Modulates Inflammation and LV Structure/Function in a Stress-Induced Cardiomyopathy Model.

程序性死亡 1 信号轴在应激诱发的心肌病模型中调节炎症和左心室结构/功能。

DOI：
发表时间：
2022-11
期刊：
影响因子：
0
作者：
Hayashi, Tomohiro;Tiwary, Sajal K;Lavine, Kory J;Acharya, Sandeep;Brent, Michael;Adamo, Luigi;Kovacs, Attila;Mann, Douglas L
通讯作者：
Mann, Douglas L

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针对肺动脉高压的炎症：是时候忘记肺部了吗？