Cardiomyocyte-specific depletion of integrin α3 preserves cardiac function after myocardial infarction.

Integrins, a family of transmembrane receptors that mediate cell-extracellular (ECM) interactions, play a pivotal role in the heart to maintain cardiac function and tissue integrity. As they sense extracellular signals, their expression changes in a microenvironment-dependent manner. Especially following myocardial infarction (MI), several alpha integrins are upregulated. Integrin α3 (ITGA3) expression has been found upregulated after MI, yet little is known about the function of ITGA3 in cardiac tissue. To evaluate the role of ITGA3 in vivo. we generated a mouse line with cardiomyocytes-specific ITGA3 depletion (ITGA3 KO). ITGA3 KO mice were characterized under baseline conditions and after permanent LAD ligation by echocardiography. Cardiac tissue was processed for histological staining (WGA/Sirius-Red) and molecular analysis by qPCR and WB. Identified changes were proven in vitro using coculturing model of neonatal rat cardiac fibroblasts (NRCFs) with siRNA treated neonatal rat cardiomyocytes (NRCMs) lacking ITGA3. ITGA3 KO mice did not show any disadvantageous alterations in cardiac function and structure under baseline conditions. After experimental MI, cardiac function was preserved and hypertrophic response diminished in ITGA3 KO. Development of fibrosis and the induction of pathological gene program was attenuated. Mechanistically, we identified an upregulation in Hippo signalling and activation of autophagic processes (ATG5 and p62 levels as well as enhanced LC3 II/I ratios) in ITGA3 KO mice after MI, which was confirmed by in-vitro experiments of NRCMs. Our findings show that in vivo depletion of ITGA3 in adult cardiomyocytes preserves cardiac function and reduces pathological remodelling after MI. Thus, interference with ITGA3 might be a novel translational approach to improve cardiac remodelling after ischemic injury.