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.

抽象的有利影响心力衰竭自然史（HF）的治疗干预措施要么缓慢或反向左心室（LV）重塑。在某些HF患者中，射血分数降低（HFREF）反向LV重塑与免受未来临床HF事件的自由有关（“心肌恢复”），而在绝大多数患者中，LV结构/功能的初始稳定之后是进行性LV重塑和不愉快的临床结果（“心肌缓解”）。虽然恢复 LV结构和功能与HF临床过程的稳定以及逆转有关 HF表型的许多方面，它与免受未来HF事件的自由无关。了解 “补偿” HF患者的临床和生物学特征，他们已归一化或部分标准化LV 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在心力衰竭领域的需要。这项研究计划的长期目标是描述负责经历反向LV的心脏功能不稳定性的机制通过恢复LV功能进行重塑，并开发新疗法，以解决此尚未满足的疗法临床需求。探索“心肌缓解”临床现象的生物学基础，我们已经开发了一个与中等主动脉相结合的临床相关的“可逆心力衰竭”的临床前临床前模型收缩（TAC）和远端LAD连接（MI），这是引起HFREF的主要合并症工业化国家。为了“逆转” HF表型，TAC + MI小鼠是由血液动力学卸载的通过手术去除主动脉骨收缩，从而导致LV结构和功能的归一化。德国在本提案中，当脱离带状的TAC + MI小鼠（“ HF-DB”小鼠）时，会暴露于神经激素时压力，它们会产生增加LV肥大并增加LV功能障碍，类似于在恢复LV结构和功能后发展功能不稳的HFREF患者。基于我们初步观察，即在开发过程中自噬 - 溶酶体系统失调从HF恢复，我们散文测试以下三个假设：（1）自噬通量在期间受到损害 HF的发展，尽管在血液动力学卸载后，磁通量相对改善，但通量仍然“效率低下”（AIM1）；（2）有效反向LV重塑需要自噬通量（AIM 2）；（3）自噬通量不足至少部分是因为功能不稳定性的责任在反向LV重塑的心脏中发育，暴露于神经激素应激（AIM 3）。具体的 AIMS 1-3将提供有关自噬在恢复中潜在作用的明确信息血流动力卸载后的LV结构和LV功能以及功能不稳定性在病理生理相关的可逆HF模型中进行反向LV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）

Targeting Inflammation in Pulmonary Artery Hypertension: Is It Time to Forget About the Lungs?

DOI：
10.1161/circheartfailure.121.009290
发表时间：
2022-01
期刊：
Circulation. Heart failure
影响因子：
0
作者：
Mann DL
通讯作者：
Mann DL

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

DOI：
10.1016/j.jacbts.2022.05.006
发表时间：
2022-11
期刊：
JACC-BASIC TO TRANSLATIONAL SCIENCE
影响因子：
9.7
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.

Mechanisms and Models in Heart Failure: A Translational Approach.