Macrophage Expression of SPARC Contributes to Pressure-Overload Dependent Change in Collagen Content and Myocardial Stiffness

SPARC 的巨噬细胞表达有助于胶原含量和心肌硬度的压力过载依赖性变化

基本信息

批准号：
10047286
负责人：
Amy D Bradshaw
金额：
--
依托单位：
RALPH H JOHNSON VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-10-01 至 2021-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10047286
关键词：
Ablation Activities of Daily Living Address Affect Automobile Driving Biopsy Cardiac Cardiac Surgery procedures Cardiovascular system Cells Chronic Clinical Clinical Research Collagen Congestive Heart Failure Cysteine Deposition Development Diagnosis EFRAC Event Extracellular Matrix Fibroblasts Fibrosis Functional disorder Funding Healthcare Heart Heart failure Human Hypertension Hypertrophy ITGAM gene Impairment In Vitro Incidence Lead Left Methods Modeling Molecular Mus Myelogenous Myocardial Myocardium Patient Care Management Patients Play Procollagen Production Property Proteins Regulation Research Risk Factors Role Structure System Systemic hypertension Testing Time Transgenic Organisms Ventricular Ventricular Remodeling Veterans age effect age related cardiogenesis clinically relevant comorbidity coronary fibrosis diphtheria toxin receptor experimental study hypertensive heart disease improved in vivo interstitial macrophage military veteran monocyte mouse model preservation pressure prevent programs promoter recruit response translational study

项目摘要

The development of myocardial remodeling and abnormal diastolic function are critical events that impact both functional capacity and the rates of morbid and mortal events in our Veteran population with chronic heart failure (CHF). CHF has a designated Quality Enhancement Research Initiative (QUERI) in the VA system to address ways to improve cardiovascular healthcare for Veteran’s suffering from CHF. Chronic pressure- overload (PO), produced by systemic hypertension, represents the most frequent cause of myocardial hypertrophy and diastolic dysfunction, and the most important risk factor for the development of heart failure, particularly heart failure with a preserved ejection fraction (HFpEF). Our recent clinical studies in Veterans showed that the transition from compensated hypertensive heart disease (HHD) to decompensated HFpEF is associated with significant changes in diastolic properties including an increase in passive diastolic stiffness. Our translational studies in Veterans showed that one pivotal determinant of this increase in stiffness is an increase in interstitial collagen. Our studies in murine models of PO-induced fibrosis showed that one mechanism that controls changes in collagen accumulation is the time dependent production of the matricellular protein SPARC (secreted protein acidic and rich in cysteine) and its regulation of post-synthetic collagen processing. Preliminary studies presented in this application support the hypothesis that myocardial macrophages serve a fundamental role in affecting the time-dependent increase in matricellular proteins that increases post synthetic collagen processing, collagen content, and myocardial stiffness in PO and contributes to the development of heart failure. This hypothesis will be tested with 3 Specific Aims. In Aim 1, the use of clinically relevant murine models of PO-induced fibrosis will be used to 1) determine whether increases in myocardial macrophages plays a causal role in driving post-synthetic collagen processing that results in myocardial fibrosis and diastolic dysfunction and 2) whether there is a time-dependent increase in myocardial macrophages after imposition of PO. Experiments in Aim 2 will determine whether cell-specific inhibition of SPARC expression in monocyte/macrophages versus targeted inhibition of SPARC in fibroblasts reduces and/or reverses PO-induced myocardial fibrosis and diastolic dysfunction. In Aim 3, studies to determine whether macrophage-dependent mechanisms driving diastolic dysfunction and myocardial fibrosis defined in vivo in Aims 1&2 play a causal role in fibroblasts isolated from PO hearts and in fibroblasts isolated from Veterans with and without HHD-induced fibrosis. The completion of these Specific Aims will lead to a better understanding of the molecular and cellular mechanisms that contribute to the development of diastolic dysfunction in PO and that lead to the transition to HFpEF. Elucidation of mechanistic factors that contribute to HFpEF are critical for improved methods of diagnosis and the development of better therapies to treat our Veterans with CHF, a significant unmet need.

心肌重塑和异常舒张功能的发展是影响两者的关键事件在我们的老兵人群中，功能能力以及病态和致命事件的发生率失败（CHF）。 CHF在VA系统中具有指定的质量增强研究计划（QUERI）解决改善老兵患有CHF的心血管医疗保健的方法。慢性压力 - 由全身性高血压产生的超负荷（PO）代表了心肌最常见的原因肥大和舒张功能障碍，以及心力衰竭发展的最重要危险因素，特别是心力衰竭，并保留了射血分数（HFPEF）。我们最近在退伍军人的临床研究表明从补偿高血压心脏病（HHD）到代偿HFPEF的过渡是与舒张特性的显着变化相关，包括增加被动舒张性刚度。我们对退伍军人的翻译研究表明，刚度增加的一个关键确定剂是间质胶原蛋白的增加。我们在PO诱导的纤维化的鼠模型中的研究表明控制胶原蛋白积累变化的机制是依赖时间的产生基质蛋白SPARC（分泌的蛋白质酸性和富含半胱氨酸）及其对合成后的调节胶原蛋白处理。本申请中介绍的初步研究支持了心肌的假设巨噬细胞在影响矩阵的时间依赖性增加中起着基本作用在合成胶原加工，胶原蛋白含量和心肌刚度增加后增加的蛋白质在PO中，有助于心力衰竭的发展。该假设将通过3个特定目标。在AIM 1中，使用PO诱导的纤维化的临床相关鼠模型将用于1）确定心肌巨噬细胞的增加是否在驱动合成后胶原蛋白加工中起因果作用这会导致心肌纤维化和舒张功能障碍，以及2）时间依赖性增加施加PO后，在心肌巨噬细胞中。 AIM 2中的实验将确定细胞特异性单核细胞/巨噬细胞中SPARC表达的抑制与成纤维细胞中SPARC的靶向抑制减少和/或逆转可引起的心肌纤维化和舒张功能障碍。在AIM 3中，研究确定巨噬细胞依赖的机制是否驱动舒张功能障碍和心肌纤维化 AIMS 1和2中的体内定义在从PO心脏隔离和成纤维细胞隔离的成纤维细胞中起因果作用来自有或没有HHD诱导纤维化的退伍军人。这些特定目标的完成将导致更好地了解有助于舒张期发展的分子和细胞机制 PO的功能障碍，这导致过渡到HFPEF。阐明有助于 HFPEF对于改进诊断方法和开发更好的治疗方法至关重要具有CHF的退伍军人，这是一个很大的未满足需求。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

And the band played on: persistent fibrosis after unbanding reveals sex-dependent differences in rats.

束带继续发挥作用：解带后的持续纤维化揭示了大鼠的性别依赖性差异。

DOI：
10.1152/ajpheart.00327.2022
发表时间：
2022
期刊：
American journal of physiology. Heart and circulatory physiology
影响因子：
0
作者：
Zile,MichaelR;Bradshaw,AmyD
通讯作者：
Bradshaw,AmyD

Cross your heart? Collagen cross-links in cardiac health and disease.

DOI：
10.1016/j.cellsig.2020.109889
发表时间：
2021-03
期刊：
Cellular signalling
影响因子：
4.8
作者：
Neff LS;Bradshaw AD
通讯作者：
Bradshaw AD

Mechanisms that limit regression of myocardial fibrosis following removal of left ventricular pressure overload.

消除左心室压力超负荷后限制心肌纤维化消退的机制。

DOI：
10.1152/ajpheart.00148.2022
发表时间：
2022
期刊：
American journal of physiology. Heart and circulatory physiology
影响因子：
0
作者：
Neff,LilyS;Zhang,Yuhua;VanLaer,AnO;Baicu,CatalinF;Karavan,Mark;Zile,MichaelR;Bradshaw,AmyD
通讯作者：
Bradshaw,AmyD

From Systemic Inflammation to Myocardial Fibrosis: The Heart Failure With Preserved Ejection Fraction Paradigm Revisited.