This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 116/25/2976    most recent CIRCULATIONAHA.107.707257v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chang, L. Articles by Chen, Y. E. Search for Related Content PubMed PubMed Citation Articles by Chang, L. Articles by Chen, Y. E. Related Collections Animal models of human disease Genetically altered mice Heart failure - basic studies Hypertrophy Myocardial cardiomyopathy disease Type 2 diabetes

(Circulation. 2007;116:2976-2983.)
© 2007 American Heart Association, Inc.

Molecular Cardiology

Rad GTPase Deficiency Leads to Cardiac Hypertrophy

Lin Chang, MD, PhD^*; Jifeng Zhang, MS^*; Yu-Hua Tseng, PhD; Chang-Qing Xie, MD, PhD; Jacob Ilany, MD; Jens C. Brüning, PhD; Zhongcui Sun, MD; Xiaojun Zhu, MD; Taixing Cui, MD, PhD; Keith A. Youker, PhD; Qinglin Yang, MD, PhD; Sharlene M. Day, MD; C. Ronald Kahn, MD; Y. Eugene Chen, MD, PhD

From the Cardiovascular Center (L.C., J.Z., C.-Q.X., T.C., S.M.D., Y.E.C.), Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Mich; Joslin Diabetes Center (Y.-H.T., J.I., J.C.B., C.R.K.), Harvard Medical School, Boston, Mass; Institute of Molecular Medicine (Z.S., X.Z.), Peking University, Beijing, People’s Republic of China; Department of Cardiology (K.A.Y.), The Methodist Hospital Research Institute, Houston, Tex; and Cardiovascular Research Institute (Q.Y.), Morehouse School of Medicine, Atlanta, Ga.

Correspondence to Jifeng Zhang or Dr Y. Eugene Chen, Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109. E-mail jifengz{at}umich.edu or echenum@umich.edu

Received April 2, 2007; accepted September 25, 2007.

Background— Rad (Ras associated with diabetes) GTPase is the prototypic member of a subfamily of Ras-related small G proteins. The aim of the present study was to define whether Rad plays an important role in mediating cardiac hypertrophy.

Methods and Results— We document for the first time that levels of Rad mRNA and protein were decreased significantly in human failing hearts (n=10) compared with normal hearts (n=3; P<0.01). Similarly, Rad expression was decreased significantly in cardiac hypertrophy induced by pressure overload and in cultured cardiomyocytes with hypertrophy induced by 10 µmol/L phenylephrine. Gain and loss of Rad function in cardiomyocytes significantly inhibited and increased phenylephrine-induced hypertrophy, respectively. In addition, activation of calcium-calmodulin–dependent kinase II (CaMKII), a strong inducer of cardiac hypertrophy, was significantly inhibited by Rad overexpression. Conversely, downregulation of CaMKII by RNA interference technology attenuated the phenylephrine-induced hypertrophic response in cardiomyocytes in which Rad was also knocked down. To further elucidate the potential role of Rad in vivo, we generated Rad-deficient mice and demonstrated that they were more susceptible to cardiac hypertrophy associated with increased CaMKII phosphorylation than wild-type littermate controls.

Conclusions— The present data document for the first time that Rad is a novel mediator that inhibits cardiac hypertrophy through the CaMKII pathway. The present study will have significant implications for understanding the mechanisms of cardiac hypertrophy and setting the basis for the development of new strategies for treatment of cardiac hypertrophy.

---

 

CLINICAL PERSPECTIVE

This article has been cited by other articles:

				M. Metrich, A. Lucas, M. Gastineau, J.-L. Samuel, C. Heymes, E. Morel, and F. Lezoualc'h Epac Mediates {beta}-Adrenergic Receptor-Induced Cardiomyocyte Hypertrophy Circ. Res., April 25, 2008; 102(8): 959 - 965. [Abstract] [Full Text] [PDF]