Differential effects of calpain inhibitors on hypertrophy of cardiomyocytes.
Two inhibitors of the calcium-dependent cysteine protease, calpain, have markedly different effects on the extent of hypertrophy induced by the alpha-adrenergic agonist, phenylephrine, of cultured neonatal rat ventricular myocytes. E64c, an inhibitor of calpain and other cysteine proteases, stimulated the hypertrophy by 59%. PD 150606, a specific calpain inhibitor, reduced the hypertrophy by 38%. Phenylephrine decreased the proteolysis of a calpain substrate by the cells 1-2 h after its addition but not at 24 h. PD 150606 inhibited proteolytic activity at all times, and the combination of phenylephrine and PD 150606 did not give greater inhibition. This suggests that cysteine proteases of the papain sub-family are involved with the hypertrophic response at two points, promoting hypertrophy at the first and limiting it at the second. Calpain appears to be the protease involved at the first point, and there may be another cysteine protease acting at the second site.
Department of Surgery, Creighton University School of Medicine, Omaha, NE 68131, USA.
Jay R
JR
Pollack
Richard C
RC
Witt
Jeffrey T
JT
Sugimoto
D000179:Acrylates / Q000494:pharmacology; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D002154:Calpain / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism*; D006332:Cardiomegaly / Q000201:enzymology* / Q000503:physiopathology; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D006023:Glycoproteins / Q000494:pharmacology*; D006352:Heart Ventricles / Q000166:cytology; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects*
D000179:Acrylates; D000316:Adrenergic alpha-Agonists; D015853:Cysteine Proteinase Inhibitors; D006023:Glycoproteins; C100442:PD 150606; C039304:calpain inhibitors; D010656:Phenylephrine; C032425:N-(N-(3-carboxyoxirane-2-carbonyl)leucyl)isoamylamine; D002154:Calpain; D007930:Leucine