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

> **NIH VA I01** · RALPH H JOHNSON VA MEDICAL CENTER · 2020 · —

## Abstract

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
HF...

## Key facts

- **NIH application ID:** 9814120
- **Project number:** 5I01CX001608-03
- **Recipient organization:** RALPH H JOHNSON VA MEDICAL CENTER
- **Principal Investigator:** Amy D Bradshaw
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-10-01 → 2021-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9814120

## Citation

> US National Institutes of Health, RePORTER application 9814120, Macrophage Expression of SPARC Contributes to Pressure-Overload Dependent Change in Collagen Content and Myocardial Stiffness (5I01CX001608-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9814120. Licensed CC0.

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