A role for caspase-1 in heart failure.
Apoptosis of cardiomyocytes is increased in heart failure and has been implicated in disease progression. The activation of "proapoptotic" caspases represents a key step in cardiomyocyte apoptosis. In contrast, the role of "proinflammatory" caspases (caspases 1, 4, 5, 11, 12) is unclear. Here, we study the cardiac function of caspase-1. Gene array analysis in a murine heart failure model showed upregulation of myocardial caspase-1. In addition, we found increased expression of caspase-1 protein in murine and human heart failure. Mice with cardiomyocyte-specific overexpression of caspase-1 developed heart failure in the absence of detectable formation of interleukin (IL)-1beta or IL-18 and inflammation. Transgenic caspase-1 induced primary cardiomyocyte apoptosis before structural and molecular signs of myocardial remodeling occurred. In contrast, deletion of endogenous caspase-1 was beneficial in the setting of myocardial infarction-induced heart failure. Furthermore, caspase-1-deficient mice were protected from ischemia/reperfusion-induced cardiomyocyte apoptosis. Studies in primary rat cardiomyocytes indicated that caspase-1 induces cardiomyocyte apoptosis primarily through activation of caspases-3 and -9. In contrast to previous findings, which imply a proinflammatory role of caspase-1, these data suggest a primary proapoptotic role for caspase-1 in cardiomyocytes. Our findings support a functional role for caspase-1-mediated myocardial apoptosis contributing to the progression of heart failure.
Merkle
Sabine
S
Rudolf Virchow Center, Deutsche Forschungsgemeinschaft-Research Center for Experimental Biomedicine, Wuerzburg, Germany.
Frantz
Stefan
S
Schön
Michael P
MP
Bauersachs
Johann
J
Buitrago
Monika
M
Frost
Robert J A
RJ
Schmitteckert
Eva M
EM
Lohse
Martin J
MJ
Engelhardt
Stefan
S
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D020170:Caspase 1 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D053148:Caspase 3 / Q000502:physiology; D053453:Caspase 9 / Q000502:physiology; D002478:Cells, Cultured; D018450:Disease Progression; D005260:Female; D006333:Heart Failure / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000473:pathology; D051381:Rats; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology
D053148:Caspase 3; D053453:Caspase 9; D020170:Caspase 1