Collagen matricryptin promotes cardiac function by mediating scar formation.

Gabriel A Grilo, Sirin N Cakir, Patti R Shaver, Rugmani P Iyer, Kaitlin Whitehead, Joseph M McClung, Ali Vahdati, Lisandra E de Castro Brás

Life sciences 2023 May 15

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A peptide mimetic of a collagen-derived matricryptin (p1159) was shown to reduce left ventricular (LV) dilation and fibrosis after 7 days delivery in a mouse model of myocardial infarction (MI). This suggested p1159 long-term treatment post-MI could have beneficial effects and reduce/prevent adverse LV remodeling. This study aimed to test the potential of p1159 to reduce adverse cardiac remodeling in a chronic MI model and to elucidate p1159 mode-of-action. Using a permanent occlusion MI rodent model, animals received p1159 or vehicle solution up to 28 days. We assessed peptide treatment effects on scar composition and structure and on systolic function. To assess peptide effects on scar vascularization, a cohort of mice were injected with Griffonia simplicifolia isolectin-B4. To investigate p1159 mode-of-action, LV fibroblasts from naïve animals were treated with increasing doses of p1159. Matricryptin p1159 significantly improved systolic function post-MI (2-fold greater EF compared to controls) by reducing left ventricular dilation and inducing the formation of a compliant and organized infarct scar, which promoted LV contractility and preserved the structural integrity of the heart. Specifically, infarcted scars from p1159-treated animals displayed collagen fibers aligned parallel to the epicardium, to resist circumferential stretching, with reduced levels of cross-linking, and improved tissue perfusion. In addition, we found that p1159 increases cardiac fibroblast migration by activating RhoA pathways via the membrane receptor integrin α4. Our data indicate p1159 treatment reduced adverse LV remodeling post-MI by modulating the deposition, arrangement, and perfusion of the fibrotic scar. Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.

Citation

Gabriel A Grilo, Sirin N Cakir, Patti R Shaver, Rugmani P Iyer, Kaitlin Whitehead, Joseph M McClung, Ali Vahdati, Lisandra E de Castro Brás. Collagen matricryptin promotes cardiac function by mediating scar formation. Life sciences. 2023 May 15;321:121598