Expression of Proto-oncogenes and Gene Mutation of Sarcomeric Proteins in Patients With Hypertrophic Cardiomyopathy

From the Cardiovascular Research Institute, Kurume University (H. Kai, H.N., H. Kato) and the Third Department of Internal Medicine (A.M., Y. Sugui, Y. Seki, F.K., T.I.), Kurume University School of Medicine, Kurume, Japan, and the Department of Tissue Physiology, Division of Adult Disease, Medical Research Institute, Tokyo Medical and Dental College (A.K.), Tokyo, Japan.

Correspondence to Hisashi Kai, MD, PhD, Third Department of Internal Medicine and the Cardiovascular Research Institute, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830-0011, Japan. E-mail kaihm{at}kurume.ktarn.or.jp

Abstract—Several mutations of cardiac ß-myosin heavy chain (ß-MHC) gene were reported in patients with hypertrophic cardiomyopathy (HCM). Involvement of proto-oncogenes has been shown in the mechanism of experimental cardiac hypertrophy. This study sought to examine the effects of c-H-ras and c-myc expression in the steady-state myocardium on hypertrophic changes and to evaluate the possible interaction between ß-MHC mutation and proto-oncogene expression in HCM. Endomyocardial biopsy was performed in 17 HCM patients (5 ß-MHC mutations and 1 troponin T mutation) and 7 control subjects (no mutation). Reverse transcription–polymerase chain reaction analysis revealed c-H-ras expression in all members of both groups. Cardiomyocyte size was correlated with the expression level of c-H-ras (P<0.001), and c-H-ras expression was upregulated in HCM patients (P<0.01). HCM patients with a ß-MHC mutation had the higher c-H-ras expression than did control subjects or patients without a mutation (P<0.01). c-myc mRNA was expressed in 7 of 17 HCM patients but not in control subjects. Myocyte size was greater in c-myc–positive HCM patients than in control subjects and c-myc–negative HCM patients (P<0.001 and P<0.05, respectively). The proto-oncogene expression did not affect clinical findings, myocardial fibrosis, or disarray. In conclusion, c-H-ras and c-myc expression in the steady-state myocardium may play a role in the hypertrophic mechanism in HCM. It is possible that ß-MHC gene mutation has some effect on the regulation of proto-oncogene expression in HCM.

Key Words: proto-oncogene • ß-myosin heavy chain mutation • hypertrophic cardiomyopathy • endomyocardial biopsy • reverse transcription–polymerase chain reaction

This article has been cited by other articles:

				H. Kudo, H. Kai, H. Kajimoto, M. Koga, N. Takayama, T. Mori, A. Ikeda, S. Yasuoka, T. Anegawa, H. Mifune, et al. Exaggerated Blood Pressure Variability Superimposed on Hypertension Aggravates Cardiac Remodeling in Rats via Angiotensin II System-Mediated Chronic Inflammation Hypertension, October 1, 2009; 54(4): 832 - 838. [Abstract] [Full Text] [PDF]

				F. Cambronero, F. Marin, V. Roldan, D. Hernandez-Romero, M. Valdes, and G. Y.H. Lip Biomarkers of pathophysiology in hypertrophic cardiomyopathy: implications for clinical management and prognosis Eur. Heart J., January 9, 2009; (2009) ehn538v1. [Abstract] [Full Text] [PDF]

				K.A. Connelly, D.J. Kelly, Y. Zhang, D.L. Prior, J. Martin, A.J. Cox, K. Thai, M.P. Feneley, J. Tsoporis, K.E. White, et al. Functional, structural and molecular aspects of diastolic heart failure in the diabetic (mRen-2)27 rat Cardiovasc Res, November 1, 2007; 76(2): 280 - 291. [Abstract] [Full Text] [PDF]

				Y. Wang Mitogen-Activated Protein Kinases in Heart Development and Diseases Circulation, September 18, 2007; 116(12): 1413 - 1423. [Abstract] [Full Text] [PDF]

				R. Roberts and U. Sigwart Current Concepts of the Pathogenesis and Treatment of Hypertrophic Cardiomyopathy Circulation, July 12, 2005; 112(2): 293 - 296. [Full Text] [PDF]

				F. Kuwahara, H. Kai, K. Tokuda, M. Takeya, A. Takeshita, K. Egashira, and T. Imaizumi Hypertensive Myocardial Fibrosis and Diastolic Dysfunction: Another Model of Inflammation? Hypertension, April 1, 2004; 43(4): 739 - 745. [Abstract] [Full Text] [PDF]

				K. Tokuda, H. Kai, F. Kuwahara, H. Yasukawa, N. Tahara, H. Kudo, K. Takemiya, M. Koga, T. Yamamoto, and T. Imaizumi Pressure-Independent Effects of Angiotensin II on Hypertensive Myocardial Fibrosis Hypertension, February 1, 2004; 43(2): 499 - 503. [Abstract] [Full Text] [PDF]

				M. Zheng, K. Dilly, J. Dos Santos Cruz, M. Li, Y. Gu, J. A. Ursitti, J. Chen, J. Ross Jr., K. R. Chien, J. W. Lederer, et al. Sarcoplasmic reticulum calcium defect in Ras-induced hypertrophic cardiomyopathy heart Am J Physiol Heart Circ Physiol, January 1, 2004; 286(1): H424 - H433. [Abstract] [Full Text] [PDF]

				F. Kuwahara, H. Kai, K. Tokuda, H. Niiyama, N. Tahara, K. Kusaba, K. Takemiya, A. Jalalidin, M. Koga, T. Nagata, et al. Roles of Intercellular Adhesion Molecule-1 in Hypertensive Cardiac Remodeling Hypertension, March 1, 2003; 41(3): 819 - 823. [Abstract] [Full Text] [PDF]

				J.-J. Hwang, P. D. Allen, G. C. Tseng, C.-W. Lam, L. Fananapazir, V. J. Dzau, and C.-C. Liew Microarray gene expression profiles in dilated and hypertrophic cardiomyopathic end-stage heart failure Physiol Genomics, July 12, 2002; 10(1): 31 - 44. [Abstract] [Full Text] [PDF]

				F. Kuwahara, H. Kai, K. Tokuda, M. Kai, A. Takeshita, K. Egashira, and T. Imaizumi Transforming Growth Factor-{beta} Function Blocking Prevents Myocardial Fibrosis and Diastolic Dysfunction in Pressure-Overloaded Rats Circulation, July 2, 2002; 106(1): 130 - 135. [Abstract] [Full Text] [PDF]

				A. MAASS, J.P. KONHILAS, B.L. STAUFFER, and L.A. LEINWAND From Sarcomeric Mutations to Heart Disease: Understanding Familial Hypertrophic Cardiomyopathy Cold Spring Harb Symp Quant Biol, January 1, 2002; 67(0): 409 - 416. [Abstract] [PDF]

				B.G. PETRICH, P. LIAO, and Y. WANG Using a Gene-switch Transgenic Approach to Dissect Distinct Roles of MAP Kinases in Heart Failure Cold Spring Harb Symp Quant Biol, January 1, 2002; 67(0): 429 - 438. [Abstract] [PDF]

				R. Roberts and U. Sigwart New Concepts in Hypertrophic Cardiomyopathies, Part I Circulation, October 23, 2001; 104(17): 2113 - 2116. [Full Text] [PDF]

				M. Meyer, S. U. Trost, W. F. Bluhm, H. J. Knot, E. Swanson, and W. H. Dillmann Impaired sarcoplasmic reticulum function leads to contractile dysfunction and cardiac hypertrophy Am J Physiol Heart Circ Physiol, May 1, 2001; 280(5): H2046 - H2052. [Abstract] [Full Text] [PDF]

				P. D. Ho, J.-S. Fan, N. L. Hayes, N. Saada, P. T. Palade, C. C. Glembotski, and P. M. McDonough Ras Reduces L-Type Calcium Channel Current in Cardiac Myocytes : Corrective Effects of L-Channels and SERCA2 on [Ca2+]i Regulation and Cell Morphology Circ. Res., January 19, 2001; 88(1): 63 - 69. [Abstract] [Full Text] [PDF]

				A. Sanbe, D. Nelson, J. Gulick, E. Setser, H. Osinska, X. Wang, T. E. Hewett, R. Klevitsky, E. Hayes, D. M. Warshaw, et al. In Vivo Analysis of an Essential Myosin Light Chain Mutation Linked to Familial Hypertrophic Cardiomyopathy Circ. Res., August 18, 2000; 87(4): 296 - 302. [Abstract] [Full Text] [PDF]

				A Muraishi, H Kai, K Adachi, H Nishi, and T Imaizumi Malalignment of the sarcomeric filaments in hypertrophic cardiomyopathy with cardiac myosin heavy chain gene mutation Heart, November 1, 1999; 82(5): 625 - 629. [Abstract] [Full Text]

				J. J. Hunter and K. R. Chien Signaling Pathways for Cardiac Hypertrophy and Failure N. Engl. J. Med., October 21, 1999; 341(17): 1276 - 1283. [Full Text] [PDF]