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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.

心肌重构的发展和舒张功能异常是影响两者的关键事件

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

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

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