Calpain inhibition preserves myocardial structure and function following myocardial infarction.
Cardiac pathology, such as myocardial infarction (MI), activates intracellular proteases that often trigger programmed cell death and contribute to maladaptive changes in myocardial structure and function. To test whether inhibition of calpain, a Ca(2+)-dependent cysteine protease, would prevent these changes, we used a mouse MI model. Calpeptin, an aldehydic inhibitor of calpain, was intravenously administered at 0.5 mg/kg body wt before MI induction and then at the same dose subcutaneously once per day. Both calpeptin-treated (n = 6) and untreated (n = 6) MI mice were used to study changes in myocardial structure and function after 4 days of MI, where end-diastolic volume (EDV) and left ventricular ejection fraction (EF) were measured by echocardiography. Calpain activation and programmed cell death were measured by immunohistochemistry, Western blotting, and TdT-mediated dUTP nick-end labeling (TUNEL). In MI mice, calpeptin treatment resulted in a significant improvement in EF [EF decreased from 67 + or - 2% pre-MI to 30 + or - 4% with MI only vs. 41 + or - 2% with MI + calpeptin] and attenuated the increase in EDV [EDV increased from 42 + or - 2 microl pre-MI to 73 + or - 4 microl with MI only vs. 55 + or - 4 microl with MI + calpeptin]. Furthermore, calpeptin treatment resulted in marked reduction in calpain- and caspase-3-associated changes and TUNEL staining. These studies indicate that calpain contributes to MI-induced alterations in myocardial structure and function and that it could be a potential therapeutic target in treating MI patients.
Mani
Santhosh K
SK
Division of Cardiology, Department of Medicine, Charleston, South Carolina, USA.
Balasubramanian
Sundaravadivel
S
Zavadzkas
Juozas A
JA
Jeffords
Laura B
LB
Rivers
William T
WT
Zile
Michael R
MR
Mukherjee
Rupak
R
Spinale
Francis G
FG
Kuppuswamy
Dhandapani
D
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002154:Calpain / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D004151:Dipeptides / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D051379:Mice; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction / Q000187:drug effects; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D013318:Stroke Volume / Q000187:drug effects; D013997:Time Factors; D014463:Ultrasonography; D016277:Ventricular Function, Left / Q000187:drug effects*; D020257:Ventricular Remodeling / Q000187:drug effects
D002316:Cardiotonic Agents; D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; C071482:calpeptin; D002154:Calpain; C505409:Casp3 protein, mouse; D053148:Caspase 3