Abstract
The efficacy of a novel, nonpeptidic, caspase 3/7-selective inhibitor, (S)-(+)-5-[1-(2-methoxymethylpyrrolidinyl)sulfonyl]isatin (MMPSI) for reducing ischemic injury in isolated rabbit hearts or cardiomyocytes was evaluated. MMPSI (0.1-10 microM) evoked a concentration-dependent reduction in infarct size (up to 56% vs. control; IC(50)=0.2 microM). Furthermore, apoptosis (DNA laddering, soluble nucleosomes) was reduced in the ischemic area-at-risk. MMPSI inhibited recombinant human caspase-3 with an IC(50)=1.7 microM. Apoptosis in H9c2 cells after 16-h simulated ischemia and 2-h simulated reperfusion was significantly reduced by MMPSI in a concentration-dependent manner (IC(50)=0.5 microM); similar effects were observed in isolated adult rabbit cardiomyocytes (IC(50)=1.5 microM). These data support an important role for caspase-3/7 in mediating myocardial ischemic injury. Furthermore, these data indicate that cardioprotection via caspase-3/7 inhibition is attainable via a small molecule (nonpeptidic) inhibitor, a necessary step in making this approach therapeutically viable.
MeSH terms
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Amino Acid Chloromethyl Ketones / pharmacology
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Animals
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Apoptosis / drug effects
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Caspase 3
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Caspase 7
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Caspase Inhibitors*
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Caspases / metabolism
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Cell Line
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Cells, Cultured
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Coronary Circulation / drug effects
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Cysteine Proteinase Inhibitors / pharmacology*
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Dipeptides / pharmacology
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Dose-Response Relationship, Drug
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Heart Rate / drug effects
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In Situ Nick-End Labeling
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Isatin / analogs & derivatives
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Isatin / pharmacology*
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Ketones / pharmacology
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Male
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Microscopy, Electron
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Myocardial Infarction / pathology
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Myocardial Infarction / physiopathology
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Myocardial Infarction / prevention & control
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Myocardial Ischemia / complications*
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Myocardial Reperfusion Injury / etiology
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Myocardial Reperfusion Injury / physiopathology
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Myocardial Reperfusion Injury / prevention & control*
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Myocardium / enzymology
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Myocardium / pathology
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Myocardium / ultrastructure
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Myocytes, Cardiac / drug effects
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Myocytes, Cardiac / metabolism
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Myocytes, Cardiac / pathology
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Pyrrolidines / pharmacology*
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Rabbits
Substances
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5-(1-(2-methoxymethylpyrrolidinyl)sulfonyl)isatin
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Amino Acid Chloromethyl Ketones
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Caspase Inhibitors
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Cysteine Proteinase Inhibitors
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Dipeptides
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Ketones
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N-acetyl-tyrosyl-valyl-alanyl-aspartyl chloromethyl ketone
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Pyrrolidines
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benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
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MDL 201053
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Isatin
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CASP3 protein, human
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CASP7 protein, human
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Caspase 3
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Caspase 7
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Caspases