Collagen-Based Matrix Pro-Survival miRNA and Regeneration for Improved Function of the Infracted Heart.

Tanja Sofrenovic, Drew Kuraitis, Ashraf Al Madhoun, Ali Ahmadi, Kimberly McEwan, Diba Ebadi, Branka Vulesevic, Brian McNeill, Marc Ruel, Ilona S Skerjanc, Erik Suuronen

Research output: Chapter in Book/Report/Conference proceedingConference contributionpeer-review

Abstract

Abstract
Background: We have previously used an injectable collagen matrix (+/- sialyl LewisX (sLeX)), to restore perfusion in ischemic skeletal muscle. This study sought to determine the ability of matrix therapy to support heart regeneration after myocardial infarction (MI).

Methods: MI was induced in C57BL/6J mice by left anterior descending artery ligation. One week post-MI, mice received intramyocardial injections of: 1) PBS; 2) collagen matrix; or 3) sLeX-collagen matrix. Some animals were sacrificed at 1 wk post-treatment for gene and microRNA expression analysis (n≥4). Heart function was assessed by echocardiography and tissues were harvested at 1 month (n≥14).

Results: One week post-treatment, miR-21 and miR-210 (pro-survival microRNAs) expression was greater in hearts treated with sLeX-matrix (by 96% and 40%; p≤0.02) or collagen matrix (by 45% and 33%; p≤0.01), compared to PBS. Also at this time, transcription of cardiac progenitor cell genes was increased in hearts treated with sLeX- matrix (Nkx2.5 (+39%), Sca-1 (+33%) and VEGFR2 (+35%); 0.03≤p≤0.06) or collagen (Nkx2.5 (+52%) and VEGFR2 (+26%); p≤0.05). At 1 month, both matrix treatments improved arteriole density (by ≥80%; p≤0.004), but only sLeX-matrix reduced apoptosis (33% less active caspase-3+ cells; p=0.02). The sLeX-matrix stimulated progenitor cell recruitment and cardiomyogenesis as exhibited by more Nkx2.5+, c-kit+ and connexin43+ cells in the myocardium (by 108%, 33% and 40%, respectively), also accompanied by 60% more proliferating cells (BrdU+), versus PBS (p≤0.05). Furthermore, there were less CD68+ macrophages (by ≥32%) and lower levels of IFNγ and TNFα (by ≥22%) with matrix treatments, suggesting reduced inflammation compared to PBS (p≤0.05). Functionally, compared to baseline (1 wk post-MI), ejection fraction at 1 month was improved with sLeX-matrix treatment (+2.5%), while it was preserved (+0.6%) with collagen matrix, and reduced (-3.6%) with PBS treatment (p≤0.03).

Conclusions: Matrix therapy for MI increased pro-survival microRNA expression and activated host progenitor cells for regeneration. This lead to improved cardiac function with sLeX-matrix, which may be attributed to reduced inflammation and apoptosis, and increased perfusion and cardiomyogenesis.
Original languageEnglish
Title of host publicationCirculation
Volume126
EditionA14344
Publication statusPublished - 2012

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