# Complement in the cellular microenvironment during cardiac renewal

> **NIH NIH K99** · TEXAS HEART INSTITUTE · 2024 · $97,216

## Abstract

PROJECT SUMMARY
Ischemic heart disease (IHD) is the leading cause of death worldwide, resulting in 9 million deaths
yearly. Current treatments for IHD are medications or surgical procedures to improve blood flow,
which cannot address the underlying permanent loss of cardiomyocytes (CMs) resulting from
myocardial infarction (MI). After MI, the heart undergoes fibrotic repair rather than regeneration.
This leads to maladaptive remodeling, further death of CMs, and eventual heart failure (HF) over
time. In IHD patients with HF, heart transplant becomes the only therapy. However, new cases of
HF far outpace the number of heart transplant procedures performed each year. Therefore, there
is an urgent need for therapeutics that directly address the loss of CMs. In neonatal mammalian
hearts post-MI and in adult hearts expressing active yes-associated protein 1 (YAP), a
transcriptional co-regulator of cell proliferation, CMs can re-enter the cell cycle and divide to
generate new CMs. I have uncovered that in both models, CM proliferation requires interplay
between poised CMs, cardiac fibroblasts (CFs), and tissue-resident macrophages (MPs); poised
CMs re-enter the cell cycle, while the Complement pathway, a component of innate immunity, is
activated in CFs and MPs to facilitate CM cell cycle progression and de-differentiation. Specifically,
C3 is activated in CFs and C3ar1 is activated in MPs, with C3 or C3ar1 knockout (KO) resulting
in decreased CM proliferation. The central hypothesis of this proposal is activation of
Complement alters the composition and metabolism of the cardiac microenvironment to
promote CM proliferation. The first aim investigates the direct role of C3ar1 resident MPs in CM
proliferation. C3ar1 MPs expand greatly during CM proliferation and express high levels of the
insulin growth factor pathway gene Igf1 and genes involved in extracellular matrix (ECM) turnover
such as Adam15. I will assay CM proliferation and metabolism in resident MP-specific Igf1 KO or
Adam15 KO versus Control hearts, as well as ECM composition and stiffness. In the second aim,
I will study how C3-CFs induce glycolytic metabolism within the cardiac microenvironment in
response to MI. My preliminary data show that in neonatal C3 KO hearts, CFs failed to upregulate
glycolysis after MI, resulting in impaired cardiac repair compared to Control hearts. I will use CF-
specific C3 KO and Control hearts to determine if C3 is required for CF activation and whether
the metabolic stress response in MPs is impaired after MI. Altogether, the proposed project aims
to understand the interactions between different cell types of the renewal competent niche of in
vivo models of CM proliferation. I believe that this work extends our CM-centric understanding of
proliferation and may yield new insights and directions for cardiac renewal.

## Key facts

- **NIH application ID:** 10944972
- **Project number:** 1K99HL174827-01
- **Recipient organization:** TEXAS HEART INSTITUTE
- **Principal Investigator:** Rich Gang Li
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $97,216
- **Award type:** 1
- **Project period:** 2024-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10944972

## Citation

> US National Institutes of Health, RePORTER application 10944972, Complement in the cellular microenvironment during cardiac renewal (1K99HL174827-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10944972. Licensed CC0.

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