Lack of beta3 integrin signaling contributes to calpain-mediated myocardial cell loss in pressure-overloaded myocardium.
Although cardiac hypertrophy initially ensues as a compensatory mechanism, it often culminates in congestive heart failure. Based on our earlier studies that calpain and beta3 integrin play cell death and survival roles, respectively, during pressure-overload (PO) hypertrophy, we investigated if the loss of beta3 integrin signaling is a potential mechanism for calpain-mediated cardiomyocyte death during PO. beta3 Integrin knockout (beta3) and wild-type mice were used to induce either moderate or severe PO in vivo for short-term (72-hour) and long-term (4-week) transverse aortic constriction. Whereas wild-type mice showed no changes during moderate PO at both time points, beta3 mice exhibited both enrichment of the mu-calpain isoform and programmed cell death of cardiomyocytes after 4-week PO. However, with severe PO that caused increased mortality in both mice groups, cell death was observed in wild-type mice also. To study calpain's role, calpeptin, a specific inhibitor of calpain, was administered through an osmotic mini-pump at 2.5 mg/kg per day beginning 3 days before moderate transverse aortic constriction or sham surgery. Calpeptin administration blocked both calpain enrichment and myocardial cell death in the 4-week PO beta3 mice. Because beta3 integrin contributes to cardioprotective signaling, these studies indicate that the loss of specific integrin function could be a key mechanism for calpain-mediated programmed cell death of cardiomyocytes in PO myocardium.
Cardiology Division of the Department of Medicine, Gazes Cardiac Research Institute, Medical University of South Carolina, Charleston, South Carolina 29425-2221, USA.
Geetha
G
Suryakumar
Harinath
H
Kasiganesan
Sundaravadivel
S
Balasubramanian
Dhandapani
D
Kuppuswamy
D000818:Animals; D017209:Apoptosis; D002154:Calpain / Q000378:metabolism; D006332:Cardiomegaly / Q000378:metabolism; D004151:Dipeptides; D006333:Heart Failure / Q000378:metabolism; D006984:Hypertrophy / Q000378:metabolism; D039661:Integrin beta3 / Q000378:metabolism*; D016023:Integrins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism*; D011312:Pressure; D015398:Signal Transduction
D004151:Dipeptides; D039661:Integrin beta3; D016023:Integrins; C071482:calpeptin; D002154:Calpain; C449002:mu-calpain