Cadherin-11 blocking antibody treatment improves outcomes in mice after myocardial infarction

Myocardial infarction (MI) and subsequent fibrotic remodeling strains the heart and contributes to the high prevalence of heart failure. The cells primarily responsible for scar formation after MI are cardiac fibroblasts,... [ view full abstract ]

Myocardial infarction (MI) and subsequent fibrotic remodeling strains the heart and contributes to the high prevalence of heart failure. The cells primarily responsible for scar formation after MI are cardiac fibroblasts, which express a specialized adhesion protein, cadherin-11 (CDH11) after injury. CDH11 contributes to inflammation and fibrosis in other fibrotic diseases; therefore we hypothesized that blocking CDH11 adhesion after MI would reduce inflammation-driven infarct expansion and fibrotic remodeling and improve outcomes in mice. MI was induced by ligation of a coronary artery, and mice were injected with a functional blocking antibody against CDH11 or a control IgG for 21 days. We assessed cardiac function with echocardiogram and measured changes in protein transcription by qPCR, which confirmed a significant increase in CDH11 expression after MI (A). We observed an increase in both survival and cardiac function (ejection fraction) in the blocking-antibody-treated group relative to controls (B-C). Transcription of IL-6, a pro-inflammatory cytokine, was significantly reduced in the antibody-treated group three days post-MI (D). Increasing dilation of the left ventricle observed in the control was significantly curtailed in the treated animals (E). AFM analysis of the tissue at 21 days revealed that both the infarct and periinfarct tissue is less stiff in the hearts from CDH11 antibody-treated animals (F). Our findings suggest that targeting CDH11-expressing myofibroblasts limits inflammation-driven remodeling while preserving cardiac function. This project will fully characterize phenotypic changes and tissue remodeling throughout the course of infarct healing and highlight a potential new treatment strategy for MI.