Rad GTPase deficiency leads to cardiac hypertrophy.
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.


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 micromol/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 CaMKIIdelta 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.
Chang
Lin
L
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.
Zhang
Jifeng
J
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.
Tseng
Yu-Hua
YH
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.
Xie
Chang-Qing
CQ
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.
Ilany
Jacob
J
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.
Brüning
Jens C
JC
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.
Sun
Zhongcui
Z
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.
Zhu
Xiaojun
X
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.
Cui
Taixing
T
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.
Youker
Keith A
KA
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.
Yang
Qinglin
Q
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.
Day
Sharlene M
SM
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.
Kahn
C Ronald
CR
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.
Chen
Y Eugene
YE
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.
D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D006332:Cardiomegaly / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006801:Humans; D007930:Leucine / Q000493:pharmacokinetics; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000201:enzymology*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering; D051381:Rats; D017207:Rats, Sprague-Dawley; D014316:Tritium; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism*
D012333:RNA, Messenger; D034741:RNA, Small Interfering; C084355:RRAD protein, human; C490030:Rrad protein, mouse; C490031:Rrad protein, rat; D014316:Tritium; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D018631:ras Proteins; D007930:Leucine