# Resolution of inflammation in healing myocardial infarcts

> **NIH NIH R01** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2024 · $128,900

## Abstract

ABSTRACT:
 The members of the Transforming Growth Factor (TGF)-Beta superfamily (TGF-Betas, Bone
Morphogenetic Proteins/BMPs, Growth differentiation factors/GDFs, activins, etc), play a central role in
repair, remodeling and fibrosis of the infarcted heart. TGF-Betas signal through heterotetrameric
complexes composed of two type II and two type I TGF-Beta receptors (TBetaRII and TBetaRI respectively). TBetaRI
activation transduces signals through a family of intracellular effectors, the receptor-activated Smads
(R-Smads: Smad1/2/3/5/8), or by stimulating non-Smad cascades. The profile of type 1 receptors
activated by a specific TGF-Beta superfamily member determines which downstream signaling cascade
will be activated. Traditional concepts suggest that the 3 TGF-Beta isoforms (TGF-Beta1, -Beta2 and -Beta3) signal
through Smad2 or Smad3, whereas BMPs activate Smad1 and Smad5. Studies in endothelial cells
have challenged this concept, suggesting that TGF-Betas may stimulate both Smad1 and Smad2/3
signaling, with the 2 pathways exerting antagonistic effects. We have previously demonstrated cell-
specific actions of TGF-Beta/Smad3 signaling in myocardial infarction that contribute to myofibroblast
activation, modulate cardiomyocyte survival and function, and regulate macrophage phagocytic activity,
and anti-inflammatory transition. However, the role of the Smad1 cascade in repair, remodeling and
fibrosis of the infarcted heart remains unknown, and the effects of Smad1 on phenotype and function of
immune and reparative cells has not been investigated.
 Our proposal explores the role of Smad1 signaling in repair and remodeling of the
infarcted heart. Our preliminary data show that Smad1 is activated predominantly in infarct
myofibroblasts and macrophages, but also in border zone cardiomyocytes and in pericytes. In vitro,
TGF-Beta isoforms potently activate Smad1 in cardiac reparative cells (macrophages and fibroblasts). In
vivo, our cell-specific loss-of-function experiments, revealed unanticipated anti-fibrotic effects of Smad1
in myofibroblasts and showed that in myeloid cells, Smad1 regulates the angiogenic properties of
macrophages. Accordingly, we will explore cell-specific actions of Smad1 in cardiac repair and we will
dissect the molecular mechanisms of Smad1 effects in 4 specific aims:
 Specific aim 1: to investigate the role of Smad1 in regulation of fibroblast phenotype
following MI and to explore the molecular basis for Smad1-mediated anti-fibrotic effects. RNA-
seq analysis suggests that the antifibrotic effects of Smad1 may involve competition with Smad3
signaling, or interactions with STAT6 and p53 fibrogenic pathways. The role of these mechanisms will
be investigated in vitro and in vivo.
 Specific aim 2: to study the role of macrophage Smad1 in repair and remodeling of the
infarcted heart. Our preliminary data show that macrophage-specific Smad1 perturbs repair of the
infarcted heart by restraining the angiogenic properties of macrophag...

## Key facts

- **NIH application ID:** 10991447
- **Project number:** 3R01HL085440-18S1
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Nikolaos G Frangogiannis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $128,900
- **Award type:** 3
- **Project period:** 2008-01-15 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10991447

## Citation

> US National Institutes of Health, RePORTER application 10991447, Resolution of inflammation in healing myocardial infarcts (3R01HL085440-18S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10991447. Licensed CC0.

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