Rad GTPase Deficiency Leads to Cardiac Hypertrophy

Overview

Journal Circulation

Specialty Cardiology & Vascular Diseases

Date 2007 Dec 7

PMID 18056528

Citations 47

Authors

Lin Chang

Jifeng Zhang

Yu-Hua Tseng

Chang-Qing Xie

Jacob Ilany

Jens C Bruning

Zhongcui Sun

Xiaojun Zhu

Taixing Cui

Keith A Youker

Qinglin Yang

Sharlene M Day

C Ronald Kahn

Y Eugene Chen

Affiliations

Soon will be listed here.

Abstract

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 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.

Citing Articles

Pharmacological or genetic inhibition of LTCC promotes cardiomyocyte proliferation through inhibition of calcineurin activity.

Devilee L, Salama A, Miller J, Reid J, Ou Q, Baraka N NPJ Regen Med. 2025; 10(1):1.

PMID: 39799185 PMC: 11724930. DOI: 10.1038/s41536-025-00389-z.

Roles of small GTPases in cardiac hypertrophy (Review).

Wang X, Nie X, Wang H, Ren Z Mol Med Rep. 2024; 30(5).

PMID: 39301654 PMC: 11425065. DOI: 10.3892/mmr.2024.13332.

Rad protein: An essential player in L-type Ca2+ channel localization and modulation in cardiomyocytes.

Kong C, Dries E J Gen Physiol. 2024; 156(10).

PMID: 39172109 PMC: 11344166. DOI: 10.1085/jgp.202413629.

Pharmacological or genetic inhibition of LTCC promotes cardiomyocyte proliferation through inhibition of calcineurin activity.

Devilee L, Miller J, Reid J, Salama A, Ou Q, Jamal M Res Sq. 2023; .

PMID: 38076903 PMC: 10705701. DOI: 10.21203/rs.3.rs-3552794/v1.

Decreased expression of GEM in osteoarthritis cartilage regulates chondrogenic differentiation via Wnt/β-catenin signaling.

Gan L, Deng Z, Wei Y, Li H, Zhao L J Orthop Surg Res. 2023; 18(1):751.

PMID: 37794464 PMC: 10548561. DOI: 10.1186/s13018-023-04236-z.

References

Orho M, Carlsson M, Kanninen T, Groop L . Polymorphism at the rad gene is not associated with NIDDM in Finns. Diabetes. 1996; 45(4):429-33. DOI: 10.2337/diab.45.4.429. View

Zhang R, Khoo M, Wu Y, Yang Y, Grueter C, Ni G . Calmodulin kinase II inhibition protects against structural heart disease. Nat Med. 2005; 11(4):409-17. DOI: 10.1038/nm1215. View

Anderson M . Calmodulin kinase and L-type calcium channels; a recipe for arrhythmias?. Trends Cardiovasc Med. 2004; 14(4):152-61. DOI: 10.1016/j.tcm.2004.02.005. View

Moyers J, Bilan P, Reynet C, Kahn C . Overexpression of Rad inhibits glucose uptake in cultured muscle and fat cells. J Biol Chem. 1996; 271(38):23111-6. DOI: 10.1074/jbc.271.38.23111. View

Satoh M, Ogita H, Takeshita K, Mukai Y, Kwiatkowski D, Liao J . Requirement of Rac1 in the development of cardiac hypertrophy. Proc Natl Acad Sci U S A. 2006; 103(19):7432-7. PMC: 1455410. DOI: 10.1073/pnas.0510444103. View

Ward Y, Ravichandran V, Matsumura F, Ito M, Spinelli B, Kelly K . The GTP binding proteins Gem and Rad are negative regulators of the Rho-Rho kinase pathway. J Cell Biol. 2002; 157(2):291-302. PMC: 2199248. DOI: 10.1083/jcb.200111026. View

Wickman G, Lan C, Vollrath B . Functional roles of the rho/rho kinase pathway and protein kinase C in the regulation of cerebrovascular constriction mediated by hemoglobin: relevance to subarachnoid hemorrhage and vasospasm. Circ Res. 2003; 92(7):809-16. DOI: 10.1161/01.RES.0000066663.12256.B2. View

Fu M, Zhang J, Tseng Y, Cui T, Zhu X, Xiao Y . Rad GTPase attenuates vascular lesion formation by inhibition of vascular smooth muscle cell migration. Circulation. 2005; 111(8):1071-7. DOI: 10.1161/01.CIR.0000156439.55349.AD. View

Yada H, Murata M, Shimoda K, Yuasa S, Kawaguchi H, Ieda M . Dominant negative suppression of Rad leads to QT prolongation and causes ventricular arrhythmias via modulation of L-type Ca2+ channels in the heart. Circ Res. 2007; 101(1):69-77. DOI: 10.1161/CIRCRESAHA.106.146399. View

10.

Zhang T, Brown J . Role of Ca2+/calmodulin-dependent protein kinase II in cardiac hypertrophy and heart failure. Cardiovasc Res. 2004; 63(3):476-86. DOI: 10.1016/j.cardiores.2004.04.026. View

11.

Passier R, Zeng H, Frey N, Naya F, Nicol R, McKinsey T . CaM kinase signaling induces cardiac hypertrophy and activates the MEF2 transcription factor in vivo. J Clin Invest. 2000; 105(10):1395-406. PMC: 315462. DOI: 10.1172/JCI8551. View

12.

Ward Y, Kelly K . Gem protein signaling and regulation. Methods Enzymol. 2006; 407:468-83. DOI: 10.1016/S0076-6879(05)07038-2. View

13.

Finlin B, Crump S, Satin J, Andres D . Regulation of voltage-gated calcium channel activity by the Rem and Rad GTPases. Proc Natl Acad Sci U S A. 2003; 100(24):14469-74. PMC: 283615. DOI: 10.1073/pnas.2437756100. View

14.

Meller N, Merlot S, Guda C . CZH proteins: a new family of Rho-GEFs. J Cell Sci. 2005; 118(Pt 21):4937-46. DOI: 10.1242/jcs.02671. View

15.

Peng X, Kraus M, Wei H, Shen T, Pariaut R, Alcaraz A . Inactivation of focal adhesion kinase in cardiomyocytes promotes eccentric cardiac hypertrophy and fibrosis in mice. J Clin Invest. 2005; 116(1):217-27. PMC: 1319217. DOI: 10.1172/JCI24497. View

16.

Dorin D, Cohen L, Del Villar K, Poullet P, Mohr R, Whiteway M . Kir, a novel Ras-family G-protein, induces invasive pseudohyphal growth in Saccharomyces cerevisiae. Oncogene. 1995; 11(11):2267-71. View

17.

Tobimatsu T, Fujisawa H . Tissue-specific expression of four types of rat calmodulin-dependent protein kinase II mRNAs. J Biol Chem. 1989; 264(30):17907-12. View

18.

Work L, McPhaden A, Pyne N, Pyne S, Wadsworth R, Wainwright C . Short-term local delivery of an inhibitor of Ras farnesyltransferase prevents neointima formation in vivo after porcine coronary balloon angioplasty. Circulation. 2001; 104(13):1538-43. DOI: 10.1161/hc3801.095661. View

19.

Heineke J, Molkentin J . Regulation of cardiac hypertrophy by intracellular signalling pathways. Nat Rev Mol Cell Biol. 2006; 7(8):589-600. DOI: 10.1038/nrm1983. View

20.

Morishige K, Shimokawa H, Eto Y, Kandabashi T, Miyata K, Matsumoto Y . Adenovirus-mediated transfer of dominant-negative rho-kinase induces a regression of coronary arteriosclerosis in pigs in vivo. Arterioscler Thromb Vasc Biol. 2001; 21(4):548-54. DOI: 10.1161/01.atv.21.4.548. View