Anti-integrin αv therapy improves cardiac fibrosis after myocardial infarction by blunting cardiac PW1+ stromal cells

There is currently no therapy to limit the development of cardiac fibrosis and consequent heart failure. We have recently shown that cardiac fibrosis post-myocardial infarction (MI) can be regulated by resident cardiac cells with a fibrogenic signature and identified by the expression of PW1 (Peg3). Here we identify alpha V-integrin (CD51) as an essential regulator of cardiac PW1(+) cells fibrogenic behavior. We used transcriptomic and proteomic approaches to identify specific cell-surface markers for cardiac PW1(+) cells and found that alpha V-integrin (CD51) was expressed in almost all cardiac PW1(+) cells (93%+/- 1%), predominantly as the alpha V beta 1 complex. alpha V-integrin is a subunit member of the integrin family of cell adhesion receptors and was found to activate complex of latent transforming growth factor beta (TGF beta at the surface of cardiac PW1(+) cells. Pharmacological inhibition of alpha V-integrin reduced the profibrotic action of cardiac PW1(+)CD51(+) cells and was associated with improved cardiac function and animal survival following MI coupled with a reduced infarct size and fibrotic lesion. These data identify a targetable pathway that regulates cardiac fibrosis in response to an ischemic injury and demonstrate that pharmacological inhibition of alpha V-integrin could reduce pathological outcomes following cardiac ischemia.