Published online before print July 19, 2004, doi: 10.1161/01.CIR.0000136088.18960.E6
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2004;110:412-418.)
© 2004 American Heart Association, Inc.
Original Articles |
Statins Inhibit ß-Adrenergic Receptor–Stimulated Apoptosis in Adult Rat Ventricular Myocytes via a Rac1-Dependent Mechanism
From the Cardiovascular (M.I., D.R.P., W.S.C.) and Endocrinology (Y.I.) Divisions, Department of Medicine, Boston University Medical Center, and Myocardial Biology (M.I., D.R.P., W.S.C.), Vascular Biology (T.A.), and Diabetes and Metabolism Units (Y.I.), Boston University School of Medicine, Boston, Mass.
Correspondence to Wilson S. Colucci, MD, Boston University Medical Center, 88 E Newton St, Boston, MA 02118. E-mail Wilson.Colucci{at}bmc.org
Received July 23, 2003; de novo received December 4, 2004; revision received March 17, 2004; accepted March 22, 2004.
Background— 3-Hydroxy-3-methylglutaryl coenzyme A inhibitors (statins) inhibit myocyte hypertrophy in vitro and ameliorate the progression of cardiac remodeling in vivo, possibly because of inhibition of the small GTPase Rac1. The role of Rac1 in mediating myocyte apoptosis is not known. ß-Adrenergic receptor (ßAR)-stimulated myocyte apoptosis is mediated via activation of c-Jun NH2-terminal kinase (JNK), leading to activation of the mitochondrial death pathway. We hypothesized that ßAR-stimulated apoptosis in adult rat ventricular myocyte (ARVMs) is mediated by Rac1 and inhibited by statins.
Methods and Results— ßAR stimulation increased apoptosis, as assessed by transferase-mediated nick-end labeling, from 5±1% to 24±2%. ßAR stimulation also increased Rac1 activity. Adenoviral overexpression of a dominant-negative mutant of Rac1 inhibited ßAR-stimulated apoptosis, JNK activation, cytochrome C release, and caspase-3 activation. Cerivastatin likewise inhibited the ßAR-stimulated activation of Rac1, decreased ßAR-stimulated apoptosis to 11±2%, and inhibited JNK activation, cytochrome C release, and caspase-3 activation.
Conclusions— ßAR stimulation causes Rac1 activation, which is required for myocyte apoptosis and leads to activation of JNK and the mitochondrial death pathway. Cerivastatin inhibits ßAR-stimulated activation of Rac1 and thereby inhibits JNK-dependent activation of the mitochondrial death pathway and apoptosis. The beneficial effects of statins on the myocardium may be mediated in part via inhibition of Rac1-dependent myocyte apoptosis.
Key Words: apoptosis • hydroxymethylglutaryl-CoA reductase inhibitors • myocytes • rac1 GTP-binding protein • receptors, adrenergic, beta
This article has been cited by other articles:
 |
|
 |
|
  K. Ramasubbu, J. Estep, D. L. White, A. Deswal, and D. L. Mann Experimental and clinical basis for the use of statins in patients with ischemic and nonischemic cardiomyopathy. J. Am. Coll. Cardiol., January 29, 2008; 51(4): 415 - 426. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. M. Clarke, A. Lyons, F. O'Connell, B. F. Deighan, C. E. Barry, N. G. Anyakoha, A. Nicolaou, and M. A. Lynch A Pivotal Role for Interleukin-4 in Atorvastatin-associated Neuroprotection in Rat Brain J. Biol. Chem., January 25, 2008; 283(4): 1808 - 1817. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Adachi, M. Yamamoto, and M. Suematsu Targeting NAD(P)H Oxidase: Ets-1 Regulates p47phox Circ. Res., November 9, 2007; 101(10): 962 - 964. [Full Text] [PDF]
|
|
|
|
 |
|
 S. Jin, R. M. Ray, and L. R. Johnson Rac1 mediates intestinal epithelial cell apoptosis via JNK Am J Physiol Gastrointest Liver Physiol, December 1, 2006; 291(6): G1137 - G1147. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. van der Harst, A. A. Voors, W. H. van Gilst, M. Bohm, and D. J. van Veldhuisen Statins in the treatment of chronic heart failure: Biological and clinical considerations Cardiovasc Res, August 1, 2006; 71(3): 443 - 454. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Custodis, M. Eberl, H. Kilter, M. Bohm, and U. Laufs Association of RhoGDI{alpha} with Rac1 GTPase mediates free radical production during myocardial hypertrophy Cardiovasc Res, July 15, 2006; 71(2): 342 - 351. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. H. Brown, D. P. Del Re, and M. A. Sussman The Rac and Rho Hall of Fame: A Decade of Hypertrophic Signaling Hits Circ. Res., March 31, 2006; 98(6): 730 - 742. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Belmonte, M. F. Santos, A. H. Kihara, C. Y. I. Yan, and D. E. Hamassaki Light-Induced Photoreceptor Degeneration in the Mouse Involves Activation of the Small GTPase Rac1. Invest. Ophthalmol. Vis. Sci., March 1, 2006; 47(3): 1193 - 1200. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. C. Dudley Jr, N. E. Hoch, L. A. McCann, C. Honeycutt, L. Diamandopoulos, T. Fukai, D. G. Harrison, S. I. Dikalov, and J. Langberg Atrial Fibrillation Increases Production of Superoxide by the Left Atrium and Left Atrial Appendage: Role of the NADPH and Xanthine Oxidases Circulation, August 30, 2005; 112(9): 1266 - 1273. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Arnaud, F. Burger, S. Steffens, N. R. Veillard, T. H. Nguyen, D. Trono, and F. Mach Statins Reduce Interleukin-6-Induced C-Reactive Protein in Human Hepatocytes: New Evidence for Direct Antiinflammatory Effects of Statins Arterioscler. Thromb. Vasc. Biol., June 1, 2005; 25(6): 1231 - 1236. [Abstract] [Full Text] [PDF]
|
|