Guanosine triphosphatase activation occurs downstream of calcineurin in cardiac hypertrophy*.
There is great interest in deciphering mechanisms of maladaptive remodeling in cardiac hypertrophy in the hope of affording clinical benefit. Potential targets of therapeutic intervention include the cytoplasmic phosphatase calcineurin and small guanosine triphosphate-binding proteins, such as Rac1 and RhoA, all of which have been implicated in maladaptive hypertrophy. However, little is known about the interaction-if any-between these important signaling molecules in hypertrophic heart disease. In this study, we examined the molecular interplay among these molecules, finding that Rho family guanosine triphosphatase signaling occurs either downstream of calcineurin or as a required, parallel pathway. It has been shown that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition blocks hypertrophy, and we report here that "statin" therapy effectively suppresses small G protein activation and blunts hypertrophic growth in vitro and in vivo. Importantly, despite significant suppression of hypertrophy, clinical and hemodynamic markers remained compensated, suggesting that the hypertrophic growth induced by this pathway is not required to maintain circulatory performance.
Richardson
Kenneth E
KE
Molecular Biology Interdisciplinary Program, Univerity of Iowa Carver College of Medicine, Iwoa City, IA, USA.
Tannous
Paul
P
Berenji
Kambeez
K
Nolan
Bridgid
B
Bayless
Kayla J
KJ
Davis
George E
GE
Rothermel
Beverly A
BA
Hill
Joseph A
JA
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D019703:Calcineurin / Q000378:metabolism*; D006332:Cardiomegaly / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control; D002478:Cells, Cultured; D004789:Enzyme Activation; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009320:Atrial Natriuretic Factor; D019703:Calcineurin; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins