Collagen‐derived matricryptin reduces cardiac dysfunction post‐MI via integrin alpha 4
Authors: Grilo Gabriel , Shaver Patti , Iyer Rugmani , de Castro Brás Lisandra 
Published: April 2020

Adverse cardiac remodeling post myocardial infarction (MI) triggers a compensatory maladaptive cardiac response that contributes to heart failure. The infarcted area is replaced by a fibrotic scar that favors collagen deposition instead of its degradation. The evolution of the scar formation depends on the interaction between cardiac cells, particularly fibroblasts, and the extracellular matrix (ECM). Matricryptins are biologically active peptides, generated from ECM proteolysis, able to regulate cell function and survival. We recently identified a collagen‐derived matricryptin (p1158/59) that gradually forms post‐MI. p1158/59 plasma levels negatively correlate with left ventricle (LV) filling pressure, suggesting a beneficial effect for this matricryptin. p1158/59 stimulates LV fibroblast migration in vitro, and mice treated with p1158/59 for 7 days post‐MI displayed less collagen deposition and reduced LV dilation. Accordingly, our goal was to identify the fibroblast receptor(s) involved in p1158/59 actions on cell migration and ECM secretion responsible for the beneficial effects observed on LV remodeling. Additionally, we aim to establish the therapeutic potential of p1158/59 in long term cardiac remodeling.

Methods

Using LV and NIH 3T3 fibroblasts, we performed automatic migration assays with increasing doses of p1158/59 to evaluate changes in receptor gene expression. Blocking antibodies against integrins were used to validate the receptor's findings. We used a murine permanent occlusion MI model (male and female C57Bl/6 mice 3–5 months old, n=4–6/group) to assess effects of p1158/59 treatment (950 μg/day for 14 days), and cardiac function was assessed by serial echocardiography (D0, D7, D14).

Results

Cardiac fibroblasts incubated for 24h with 100nM p1158/59 displayed >2‐fold increase of several integrins, with the highest increase on integrin a4 (Itga4), suggesting it as a receptor for p1158/59. Using a migration assay, fibroblasts were incubated with p1158/59 100nM ± Itga4 blocking antibody (15μg/mL) for 2h before wound. The antibody abolished the pro‐migratory effects of the matricryptin, indicating Itga4 as the receptor for p1158/59. Echocardiography analysis demonstrated that mice treated with p1158/59 post‐MI had an increase of 42% in ejection fraction, compared to controls. Additionally, cardiac output exceeded 50% when compared to vehicle controls. These results indicate that p1158/59 attenuated cardiac dysfunction post‐MI.

Conclusion

Our data suggest that matricryptin p11/58/59 treatment reduces maladaptive LV remodeling post‐MI. Noteworthy, p1158/59 beneficial effects occur through activation of signaling pathways in cardiac fibroblasts via the receptor Itga4.

Support or Funding Information

We acknowledge support from the American Heart Association (18AIREA33960311 and 19PRE34450066) and the Research and Graduate School at East Carolina University.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.