Document Detail

Caspase inhibition modulates left ventricular remodeling following myocardial infarction through cellular and extracellular mechanisms.
MedLine Citation:
PMID:  20147844     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Myocyte death occurs by necrosis and caspase-mediated apoptosis in myocardial infarction (MI). In vitro studies suggest caspase activation causes myocardial contractile protein degradation without inducing apoptosis. Thus, caspase activation may evoke left ventricular (LV) remodeling through independent processes post-MI. The effects of caspase activation on LV geometry post-MI remain unclear. This project applied pharmacologic caspase inhibition (CASPI) to a porcine model of MI.
METHODS AND RESULTS: Pigs (34 kg) were instrumented to induce 60 minutes of coronary artery occlusion followed by reperfusion and a 7-day follow-up period. Upon reperfusion, the pigs were randomized to saline (n = 12) or CASPI (n = 10, IDN6734, 6 mg/kg i.v., then 6 mg/kg/h for 24 hours). Plasma troponin-I values were reduced with CASPI compared with saline at 24 hours post-MI (133 +/- 15 vs. 189 +/- 20 ng/mL, respectively, P < 0.05). LV end-diastolic area (echocardiography) and interregional length (sonomicrometry) increased from baseline in both groups but were attenuated with CASPI by 40% and 90%, respectively (P < 0.05). Myocyte length was reduced with CASPI compared with saline (128 +/- 3 vs. 141 +/- 4 microm, respectively, P < 0.05). Plasma-free pro-matrix metalloproteinase-2 values increased from baseline with CASPI (27% +/- 6%, P < 0.05) indicative of reduced conversion to active MMP-2. Separate in vitro studies demonstrated that activated caspase species cleaved pro-MMP-2 yielding active MMP-2 forms and that MMP activity was increased in the presence of activated caspase-3.
CONCLUSIONS: CASPI attenuated regional and global LV remodeling post-MI and altered viable myocyte geometry. Caspases increased MMP activity in vitro, whereas CASPI modified conversion of MMP-2 to the active form in vivo. Taken together, the results of the present study suggest that the elaboration of caspases post-MI likely contribute to LV remodeling through both cellular and extracellular mechanisms.
William M Yarbrough; Rupak Mukherjee; Robert E Stroud; Evan C Meyer; G Patricia Escobar; Jeffrey A Sample; Jennifer W Hendrick; Joseph T Mingoia; Francis G Spinale
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  Journal of cardiovascular pharmacology     Volume:  55     ISSN:  1533-4023     ISO Abbreviation:  J. Cardiovasc. Pharmacol.     Publication Date:  2010 Apr 
Date Detail:
Created Date:  2010-04-21     Completed Date:  2010-09-27     Revised Date:  2014-09-18    
Medline Journal Info:
Nlm Unique ID:  7902492     Medline TA:  J Cardiovasc Pharmacol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  408-16     Citation Subset:  IM    
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MeSH Terms
Actins / metabolism
Blood Pressure / drug effects,  physiology
Caspase 3 / metabolism,  pharmacology
Caspase Inhibitors*
Caspases / metabolism*,  pharmacology
Collagen / metabolism
Cysteine Proteinase Inhibitors / pharmacology*
Enzyme Precursors / metabolism
Gelatinases / metabolism
Heart / drug effects,  physiopathology
Heart Ventricles / drug effects,  metabolism,  pathology
Matrix Metalloproteinases / metabolism
Myocardial Infarction / blood,  metabolism*,  pathology,  physiopathology
Myocardium / metabolism,  pathology
Myocytes, Cardiac / drug effects,  pathology
Myosins / metabolism
Oligopeptides / pharmacology
Recombinant Proteins / metabolism
Sus scrofa
Troponin / metabolism
Troponin I / blood,  metabolism
Ventricular Dysfunction, Left / physiopathology
Ventricular Remodeling / drug effects*
Grant Support
Reg. No./Substance:
0/Actins; 0/Caspase Inhibitors; 0/Cysteine Proteinase Inhibitors; 0/Enzyme Precursors; 0/Oligopeptides; 0/Recombinant Proteins; 0/Troponin; 0/Troponin I; 0/benzyloxycarbonyl-valyl-alanyl-aspartic acid; 9007-34-5/Collagen; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspases; EC 3.4.24.-/Gelatinases; EC 3.4.24.-/Matrix Metalloproteinases; EC 3.4.24.-/progelatinase; EC

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