# Cardioprotection and uncoupling myofibroblast-myocyte communications

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2022 · $393,750

## Abstract

PROJECT SUMMARY/ABSTRACT
In response to damage, pathological cardiac remodeling frequently manifests as myocardial hypertrophy,
fibrosis, contractile dysfunction and/or increased arrhythmia vulnerability. Myofibroblasts (Mfbs) are not normally
present in the working myocardium but accumulate in large numbers in the injured heart. Hypersecretion of
collagen and paracrine factors from activated Mfbs results in the formation of electrically insulating septa and
ionic remodeling of cardiomyocytes (CMs), respectively, promoting arrhythmia. Besides their barrier and
paracrine function, preliminary experiments using intravital voltage imaging and immunohistochemistry, suggest
the intriguing possibility that Mfbs influence the functional properties of fibrotically remodeled myocardium via
direct electrotonic interactions with surrounding CMs via gap junctions composed of cell-to-cell Connexin(Cx)43
subunits. Preliminary mouse modeling data also revealed that chronic systemic infusion of β-adrenergic or
angiotensin-II receptor agonists, as well as acute myocardial infarction (MI) result in Mfb-restricted misexpression
of Cx43, a stretch-induced profibrotic cytokine Ccl2 (MCP-1) and profibrotic matricellular Periostin (Postn)
coincident with pathological remodeling. Likewise, in patients with acute MI or pressure overload, POSTN and
MCP-1 are robustly upregulated and Cx43 (GJA1) distribution is perturbed. Cx43, the principal gap junction
protein responsible for action potential propagation in ventricles, is often mis-expressed in hypertrophied and
ischemic patient hearts. We and others have demonstrated that Cx43 is also present in the pathological Mfb
population, and additional preliminary data revealed Ccl2 is transcribed in Mfbs (whereas its receptor Ccr2 is in
CMs). Endogenous Postn functionally promotes cardiac fibrosis/ventricular stiffness, as surviving Postn nulls
exhibit less fibrosis and better function after MI. Moreover, we generated a unique 3.9kb-driven Postn enhancer
reporter line that drives Cre-recombinase expression only in Mfbs in injured hearts (designated Postn-Cre). Thus,
this is a most useful tool for genetic manipulation of cardiac activated injury-site Mfbs. However, the actual role
that electrical coupling in Postn-expressing Mfb-lineage plays and the mechanism underlying Mfb-CM
interactions during pathological remodeling remain unknown. Thus, three interrelated aims are proposed to
examine these preliminary data. Aim 1 will test the hypothesis that uncoupling Mfb-CM electrical signaling via
Mfb-restricted cKO of Cx43 prevents adverse cardiac remodeling. Aim 2 will test whether Mfb-restricted Cx43
cKO offers arrhythmia protection. Aim 3 will determine if Mfb-restricted loss of the Ccl2 cytokine ameliorates
adjacent CM contractile dysfunction.

## Key facts

- **NIH application ID:** 10430147
- **Project number:** 5R01HL148165-04
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Simon James Conway
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $393,750
- **Award type:** 5
- **Project period:** 2019-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10430147

## Citation

> US National Institutes of Health, RePORTER application 10430147, Cardioprotection and uncoupling myofibroblast-myocyte communications (5R01HL148165-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10430147. Licensed CC0.

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