# Collagen-derived peptides to target inflammation in myocardial infarction

> **NIH NIH R56** · EAST CAROLINA UNIVERSITY · 2020 · $366,494

## Abstract

Abstract
 Myocardial infarction (MI) leads to the generation of a scar that is mostly constituted by cardiac extracellular
matrix (ECM). The balance between degradation and deposition of ECM is a strong predictor of clinical
outcomes. ECM degradation occurs by matrix metalloproteinases (MMPs); and ECM deposition occurs by
cardiac fibroblasts. Uncontrolled ECM degradation exacerbates inflammation and uncontrolled deposition leads
to a fibrotic, stiff myocardium. Both ECM degradation and deposition promote adverse remodeling and
progression to heart failure. Within the MMP family, MMP-9 has been reported as a prognostic indicator of
cardiac dysfunction in myocardial infarction (MI) patients; as MMP-9 levels directly associate with patient
mortality. Thus, the advantage of inhibiting MMP-9 after MI has been long recognized. However, clinical trials
using global MMP-9 inhibition have mostly failed both due to lack of MMP inhibitor specificity and importance of
MMP-9 in several essential processes.
 We recently identified an ECM-derived peptide (p1158/59) that acts as a competitive and specific MMP-9
substrate. Herein, we propose use of p1158/59 as an MMP-9 competitive substrate to reduce MMP-9 proteolytic
capacity post-MI. This approach does not inhibit MMP-9 activity but rather limits its proteolytic capacity and
therefore reduces cleavage of endogenous substrates that promote inflammation and inhibit repair. The synthetic
peptide p1158/59 is a mimetic of the naturally formed fragment C-1158/59 generated by MMP-9 cleavage of
collagen post-MI. In humans, plasma levels of endogenous C-1158/59 post-MI correlate with lower left ventricle
filling pressure, indicating a therapeutic potential of C-1158/59. Indeed, mice treated with exogenous p1158/59
post-MI display less LV dilation, reduced inflammation and fibrosis, and improved cardiac function. While we
know that exogenous delivery is beneficial, how p1158/59 regulates post-MI inflammation and ECM deposition
has not been mechanistically dissected. Accordingly, the central hypothesis of this proposal is that p1158/59
blunts adverse remodeling after MI by serving as a competitive substrate to reduce MMP-9 proteolysis of
substrates necessary for promotion of inflammation and ECM deposition.
 To elucidate the mode-of-action and signaling pathways mediated by p1158/59 in the post-MI setting, we
propose to identify the mechanisms whereby p1158/59 tempers the post-MI inflammatory response, modulates
cardiac fibroblast signaling to reduce ECM secretion; and promotes macrophage-fibroblast crosstalk.

## Key facts

- **NIH application ID:** 10241717
- **Project number:** 1R56HL152297-01
- **Recipient organization:** EAST CAROLINA UNIVERSITY
- **Principal Investigator:** Lisandra E de Castro Braz
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $366,494
- **Award type:** 1
- **Project period:** 2020-09-25 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10241717

## Citation

> US National Institutes of Health, RePORTER application 10241717, Collagen-derived peptides to target inflammation in myocardial infarction (1R56HL152297-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10241717. Licensed CC0.

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