Inhibition of integrin alpha V reduces inflammation and the transition to heart failure after pressure overload.

Abstract

Integrin alpha V (CD51) is a surface receptor that binds to extracellular matrix ligands and contributes to fibrotic responses, including post-infarction myocardial fibrosis. However, its role in other forms of heart failure, particularly pressure overload-induced cardiac remodeling, remains poorly understood. This study aimed to investigate the role of CD51 in cardiac remodeling and fibrosis under pressure overload conditions and to assess the therapeutic potential of CD51 inhibition in preventing heart failure progression. Two murine pressure-overload models were established using osmotic minipumps delivering either angiotensin II (AngII) alone or in combination with phenylephrine (PE). CD51 expression and CD51⁺ cell infiltration were analyzed, and the functional relevance was tested using the CD51 inhibitor cilengitide. Both models induced comparable hypertrophic remodeling at the organ and cardiomyocytes levels. However, only AngII + PE treatment resulted in significant cardiac fibrosis and pulmonary congestion, along with increased myocardial CD51 expression and CD51⁺ cell infiltration, findings not observed in the AngII-only group. CD51 expression was enriched in a subset of circulating monocytes expressing high levels of MHCII (MHCII^hi), and AngII + PE-treated hearts exhibited increased monocyte infiltration. Daily cilengitide administration significantly reduced cardiac fibrosis, limited heart failure progression, and decreased both CD51 expression in MHCII^hi monocytes and monocyte infiltration into the myocardium, independent of CCR2. CD51 contributes to the immune-fibrotic axis driving heart failure progression under pressure overload. Pharmacological inhibition of CD51 reduces cardiac fibrosis and dysfunction while modulating pro-inflammatory CD51⁺ myeloid cells, offering a novel therapeutic strategy for pressure overload-induced heart failure.