Use of cilengitide for ameliorating cardiac fibrosis occurring in response to myocardial infarction
Activated cardiac fibroblasts are essential for the production of extracellular matrix proteins that accumulate during cardiac fibrosis, and PW1 + cardiac adult stem cells were recently proposed as a cellular source of fibroblasts in the ischemic hearts. Here the inventors identify αV-integrin (or CD51) as an essential regulator of PW1 + cardiac adult stem cells fibrogenic behavior. Inhibition of αV-integrin reduce the profibrotic gene expression profile and the ability to differentiate into fibroblasts of cardiac PW1 + cells. The pharmacological blockade of αV-containing integrins improved cardiac function and survival after MI by reducing infarct size and attenuating the extension of reactive cardiac fibrosis. Notably, the total cardiac fibrotic area as well as interstitial fibrosis in the remote myocardial area are significantly reduced after pharmacological blockade of αV-containing integrins. These data identify a new mechanism that regulates cardiac fibrosis in response to an ischemic injury and suggest that pharmacological targeting of αV-integrin may provide clinical benefit in the treatment of cardiac fibrosis.
1. A method of ameliorating cardiac fibrosis in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a single αV-integrin inhibitor, wherein the αV-integrin inhibitor is cilengitide, and wherein the cardiac fibrosis occurs in response to myocardial infarction.
2. The method of claim 1 wherein the αV-integrin inhibitor limits the development of reactive interstitial fibrosis in the viable myocardium.
3. The method of claim 1 wherein the αV-integrin inhibitor improves cardiac function.
4. A method of ameliorating cardiac fibrosis in a patient suffering from acute myocardial infarction, comprising
administering to the patient a therapeutically effective amount of cilengitide, wherein administration of the cilengitide reduces differentiation of PW1+ cardiac adult stem cells into fibroblasts and limits the development of reactive interstitial fibrosis.
5. The method of claim 4 , wherein administration of the cilengitide reduces infarct size and/or attenuates extension of reactive cardiac fibrosis.
6. The method of claim 4 , wherein administration of the cilengitide improves cardiac function after acute myocardial infarction.
7. The method of claim 4 , wherein administration of cilengitide improves survival as compared to a patient suffering from acute myocardial infarction and not administered cilengitide.