Calcineurin protects the heart in a murine model of dilated cardiomyopathy.
Dilated cardiomyopathy (DCM) is a relatively common disease with a poor prognosis. Given that the only meaningful treatment for DCM is cardiac transplantation, investigators have explored the underlying molecular mechanisms of this disease in the hopes of identifying novel therapeutic targets. One such target is the serine-threonine phosphatase calcineurin, a Ca2+-activated signaling factor that is known to regulate the cardiac hypertrophic program, although its role in DCM is currently unknown. In order to address this issue, we crossed muscle lim protein (MLP) knock-out mice-a murine model of DCM-with calcineurin A beta ko mice, which lack the stress responsive isoform of calcineurin that critically regulates the cardiac hypertrophic response. Interestingly, the majority (73%) of the MLP/calcineurin A beta double knock-out mice died within 20 days of birth with signs of cardiomyopathy. Ultrastructural examination revealed enhanced cardiomyocyte apoptosis and necrosis in the postnatal myocardium of these mice. The MLP/calcineurin A beta double knock-out mice that survived until adulthood showed reduced left ventricular function, enhanced apoptotic and necrotic cardiomyocyte death and augmented myocardial fibrosis compared to various control groups. Antithetically, mild overexpression of activated calcineurin in the mouse heart improved function and adverse remodeling in MLP knock-out mice. Collectively, these results reveal an important and previously unrecognized protective function of endogenous myocardial calcineurin in a mouse model of dilated cardiomyopathy.
Department of Pediatrics, University of Cincinnati, Cincinnati Children's Hospital Medical Center, Howard Hughes Medical Institute, 240 Albert Sabin Way, Cincinnati, OH 45229, USA. Heineke.Joerg@Mh-Hannover.de
Joerg
J
Heineke
Kai C
KC
Wollert
Hanna
H
Osinska
Michelle A
MA
Sargent
Allen J
AJ
York
Jeffrey
J
Robbins
Jeffery D
JD
Molkentin
D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D002118:Calcium / Q000737:chemistry; D002311:Cardiomyopathy, Dilated / Q000378:metabolism* / Q000473:pathology*; D016923:Cell Death; D004195:Disease Models, Animal; D004452:Echocardiography; D005786:Gene Expression Regulation; D006321:Heart / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D009206:Myocardium
D019703:Calcineurin; D002118:Calcium