Original ArticleLack of β3 Integrin Signaling Contributes to Calpain-Mediated Myocardial Cell Loss in Pressure-Overloaded MyocardiumSuryakumar, Geetha PhD*; Kasiganesan, Harinath PhD*; Balasubramanian, Sundaravadivel PhD*; Kuppuswamy, Dhandapani PhD*†Author Information From the *Cardiology Division of the Department of Medicine, Gazes Cardiac Research Institute, Medical University of South Carolina, Charleston, South Carolina; and †Ralph H. Johnson Department of Veterans Affairs Medical Center, Charleston, SC. Received for publication November 9, 2009; accepted February 17, 2010. Dr. Suryakumar's present address: Defence Institute of Physiology and Allied Sciences, Ministry of Defence, Lucknow Road, Timarpur, Delhi-110054, India. This study was supported by National Institutes of Health (NIH) grant PPG HL-48788, by NIH grant RHL092124A (to D.K), by a Merit award from the Research Service of the Department of Veterans Affairs, and by a BOYSCAST fellowship from the Department of Science and Technology, India (to G.S.). The authors report no conflicts of interest. Reprints: Dhandapani Kuppuswamy, PhD, Gazes Cardiac Research Institute, 114 Doughty Street, Charleston, SC 29425-2221 (e-mail: firstname.lastname@example.org). Journal of Cardiovascular Pharmacology: June 2010 - Volume 55 - Issue 6 - p 567-573 doi: 10.1097/FJC.0b013e3181d9f5d4 Buy Metrics Abstract Although cardiac hypertrophy initially ensues as a compensatory mechanism, it often culminates in congestive heart failure. Based on our earlier studies that calpain and β3 integrin play cell death and survival roles, respectively, during pressure-overload (PO) hypertrophy, we investigated if the loss of β3 integrin signaling is a potential mechanism for calpain-mediated cardiomyocyte death during PO. β3 Integrin knockout (β3-/-) 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, β3-/- mice exhibited both enrichment of the μ-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 β3-/- mice. Because β3 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. © 2010 Lippincott Williams & Wilkins, Inc.