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Heart-specific inhibition of protooncogene c-myc attenuates cold-induced cardiac hypertrophy

Gene Therapy volume 14, pages 1406–1416 (2007)Cite this article

Abstract

The protooncogene c-myc is involved in the regulation of cell growth. Although increased c-Myc expression is found in hypertrophied hearts, the role of c-Myc in the development of cardiac hypertrophy (CH) has never been determined. The aim of this study was to test the effect of heart-specific inhibition of c-Myc expression on the development of cold-induced cardiac hypertrophy (CICH). We hypothesized that heart-specific inhibition of c-Myc expression attenuates CICH. We constructed c-Myc antisense (c-MycAS) plasmid and green fluorescent protein (GFP) plasmid driven by a heart-specific promoter, α-myosin heavy chain (MHC). The cell culture study indicated that c-MycAS can effectively inhibit c-Myc expression and that GFP can express in the rat heart cells. Four groups of rats were used to test the effect of in vivo inhibition of cardiac c-Myc expression on the development of CICH. Three groups received an intravenous injection of c-MycAS, GFP and buffer, respectively, at the beginning of exposure to moderate cold (6.7°C), while the last group received buffer and was kept at room temperature (25°C) to serve as a control. Blood pressure (BP) of the cold-exposed groups receiving buffer or GFP increased significantly, whereas BP of the c-MycAS group did not increase until 28 days after exposure to cold. Thus, c-MycAS delayed and attenuated cold-induced hypertension (CIH). The antihypertensive effect of c-MycAS was probably due to the decreased cardiac output. Magnetic resonance imaging (MRI) showed that the in vivo left ventricle wall thickness of cold-exposed rats was decreased significantly by c-MycAS. Consistently, the cold-induced increase in heart weight was attenuated by inhibition of cardiac c-Myc expression. The heart specificity of α-MHC promoter was confirmed by the selective inhibition of c-Myc expression in the heart and by the selective expression of both GFP mRNA and GFP protein in the heart. Heart-specific inhibition of c-Myc expression attenuated the development of CICH. The increased c-Myc expression may play a critical role in the pathogenesis of CICH. Thus, heart-specific inhibition of c-Myc expression may be a new and effective approach for the control of CH.

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Accession codes

Accessions

GenBank/EMBL/DDBJ

Abbreviations

MHC:

myosin heavy chain

SNS:

sympathetic nervous system

RAS:

rennin-angiotensin system

ANF:

atria natriuretic factor

OCT:

compound, optimal cutting temperature compound

NBF:

neutral-buffered formalin

ECG:

electrocardiogram.

References

  1. Chen H, Liu J, Zhao CQ, Diwan BA, Merrick BA, Waalkes MP . Association of c-myc overexpression and hyperproliferation with arsenite-induced malignant transformation. Toxicol Appl Pharmacol 2001; 175: 261–268.

    Google Scholar 

  2. Ponzielli R, Katz S, Barsyte-Lovejov D, Penn LZ . Cancer therapeutics: targeting the dark side of Myc. Eur J Cancer 2005; 41: 2485–2501.

    Article  CAS  PubMed  Google Scholar 

  3. Zimmer HG . Catecholamine-induced cardiac hypertrophy: significance of proto-oncogene expression. J Mol Med 1997; 75: 849–859.

    Article  CAS  PubMed  Google Scholar 

  4. Sadoshima J, Izumo S . Molecular characterization of angiotensin II-induced hypertrophy of cardiac myocytes and hyperplasia of cardiac fibroblasts. Critical role of the AT1 receptor subtype. Circ Res 1993; 73: 413–423.

    Article  CAS  PubMed  Google Scholar 

  5. Green NK, Gammage MD, Franklyn JA, Heagerty AM, Sheppard MC . Regulation of beta myosin heavy chain, c-myc and c-fos proto-oncogenes in thyroid hormone-induced hypertrophy of the rat myocardium. Clin Sci 1993; 84: 61–67.

    Article  CAS  Google Scholar 

  6. Izumo S, Nadal-Ginard B, Mahdavi V . Protooncogene induction and reprogramming of cardiac gene expression produced by pressure overload. Proc Natl Acad Sci USA 1988; 85: 339–343.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Xiao G, Mao S, Baumgarten G, Serrano J, Jordan MC, Roos KP et al. Inducible activation of c-Myc in adult myocardium in vivo provokes cardiac myocyte hypertrophy and reactivation of DNA synthesis. Circ Res 2001; 89: 1122–1129.

    Article  CAS  PubMed  Google Scholar 

  8. Schunkert H, Weinberg EO, Bruckschlegel G, Riegger AJ, Lorell BH . Alteration of growth responses in established cardiac pressure overload hypertrophy in rats with aortic banding. J Clin Invest 1995; 96: 2768–2774.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Roffe C, MacDiarmaid-Gordon A, Ohanian V, Hollis S, Heagerty AM . The effect of afterload and angiotensin II on proto-oncogene mRNA levels in the isolated working rat heart. Cardiovasc Res 1996; 31: 907–916.

    Article  CAS  PubMed  Google Scholar 

  10. Green NK, Franklyn JA, Ohanian V, Heagerty A, Gammage MD . Transfection of cardiac muscle: effects of overexpression of c-myc and c-fos proto-oncogene proteins in primary cultures of neonatal rat cardiac myocytes. Clin Sci 1997; 92: 181–188.

    Article  CAS  Google Scholar 

  11. Starksen NF, Simpson PC, Bishopric N, Coughlin SR, Lee WM, Escobedo JA et al. Cardiac myocyte hypertrophy is associated with c-myc protopncogene expression. Proc Natl Acad Sci USA 1986; 83: 8348–8350.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Negoro N, Inariba H, Inoue T, Kanayama Y, Takeda T . Expression of c-myc proto-oncogene in hearts and cultured smooth muscle cells of spontaneously hypertensive rats. J Hypertens Suppl 1988; 6: S128–S130.

    Article  CAS  PubMed  Google Scholar 

  13. Taketani S, Sawa Y, Taniguchi K, Mitsuno M, Kawaguchi N, Onishi S et al. C-Myc expression and its role in patients with chronic aortic regurgitation. Circulation 1997; 96: 83–87.

    Google Scholar 

  14. Taketani S, Sawa Y, Ichikawa H, Ohtake S, Nishimura M, Kawaguchi N et al. Change of c-Myc expression and cardiac hypertrophy in patients with aortic valve replacement. Ann Thorac Surg 2001; 71: 1154–1159.

    Article  CAS  PubMed  Google Scholar 

  15. Chen S, Su J, Wu K, Hu W, Gardner DG, Chen D . Early captopril treatment prevents hypertrophy dependent gene expression in hearts of SHR. Am J Physiol 1998; 274: 1511–1517.

    Article  Google Scholar 

  16. Robbins RJ, Swain JL . C-myc protooncogene modulates cardiac hypertrophic growth in transgenic mice. Am J Physiol 1992; 262: 590–597.

    Google Scholar 

  17. Hannan RD, Jenkins A, Jenkins AK, Brandenburger Y . Cardiac hypertrophy: a matter of translation. Clin Exp Pharmacol Physiol 2003; 30: 517–527.

    Article  CAS  PubMed  Google Scholar 

  18. Gyllerup S, Lanke J, Lindholm LH, Schersten B . Cold climate is an important factor in explaining regional differences in coronary mortality even if serum cholesterol and other established risk factors are taken into account. Scott Med J 1993; 38: 169–172.

    Article  CAS  PubMed  Google Scholar 

  19. Sheth T, Nair C, Muller J, Yusuf S . Increased winter mortality from acute myocardial infarction and stroke: the effect of age. J Am Coll Cardiol 1999; 33: 1916–1919.

    Article  CAS  PubMed  Google Scholar 

  20. Marchant B, Ranjadayalan K, Stevenson R, Wilkinson P, Timmis AD . Circadian and seasonal factors in the pathogenesis of acute myocardial infarction: the influence of environmental temperature. Br Heart J 1993; 69: 385–387.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Donaldson GC, Robinson D, Allaway SL . An analysis of arterial disease mortality and BUPA health screening data in men, in relation to outdoor temperature. Clin Sci Colch 1997; 92: 261–268.

    Article  CAS  PubMed  Google Scholar 

  22. Baker-Blocker A . Winter weather and cardiovascular mortality in Minneapolis-St. Paul. Am J Public Health 1982; 72: 261–265.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Seretakis D, Lagiou P, Lipwothr L, Signorello LB, Rothman KJ, Trichopoulous T . Changing seasonality of mortality from coronary heart disease. JAMA 1997; 278: 1012–1014.

    Article  CAS  PubMed  Google Scholar 

  24. Minami J, Kawano Y, Ishimitsu T, Yoshimi H, Takisita S . Seasonal variations in office, home and 24 h ambulatory blood pressure in patients with essential hypertension. J Hypertens 1996; 14: 1421–1425.

    Article  CAS  PubMed  Google Scholar 

  25. De-Lorenzo F, Sharma V, Scully M, Kakkar VV . Cold adaptation and the seasonal distribution of acute myocardial infarction. QJM 1999; 92: 747–751.

    Article  CAS  PubMed  Google Scholar 

  26. Enquselassie F, Dobson AJ, Alexander HM, Steele PL . Seasons, temperature and coronary disease. Int J Epidemiol 1993; 22: 632–636.

    Article  CAS  PubMed  Google Scholar 

  27. Fregly MJ, Kikta DC, Threatte RM, Torres JL, Barney CC . Development of hypertension in rats during chronic exposure to cold. J Appl Physiol 1989; 66: 741–749.

    Article  CAS  PubMed  Google Scholar 

  28. Sun Z, Cade R, Katovich MJ, Fregly MJ . Body fluid distribution in rats with cold-induced hypertension. Physiol Behav 1999; 65: 879–884.

    Article  CAS  PubMed  Google Scholar 

  29. Sun Z, Cade JR, Fregly MJ . Cold-induced hypertension. A model of mineralocorticoid-induced hypertension. Ann N Y Acad Sci 1997; 813: 682–688.

    Article  CAS  PubMed  Google Scholar 

  30. Sun Z, Cade JR, Fregly MJ, Rowland NE . Effect of chronic treatment with propranolol on the cardiovascular responses to chronic cold exposure. Physiol Behav 1997; 62: 379–384.

    Article  CAS  PubMed  Google Scholar 

  31. Sun Z, Fregly MJ, Cade JR . Effect of renal denervation on elevation of blood pressure in cold-exposed rats. Can J Physiol Pharmacol 1995; 73: 72–78.

    Article  CAS  PubMed  Google Scholar 

  32. Sun Z, Wang X, Wood CE, Cade JR . Genetic AT1A receptor deficiency attenuates cold-induced hypertension. Am J Physiol Regul Comp Physiol 2005; 288: R433–R439.

    Article  CAS  Google Scholar 

  33. Wang X, Cade R, Sun Z . Human eNOS gene delivery attenuates cold-induced hypertension. Am J Physiol Heart Circ Physiol 2005; 289: H1161–H1168.

    Article  CAS  PubMed  Google Scholar 

  34. Peng JF, Kimura B, Fregly MJ, Phillips MI . Reduction of cold-induced hypertension by antisense oligodeoxynucleotides to angiotensinogen mRNA and AT1-receptor mRNA in brain and blood. Hypertension 1998; 31: 1317–1323.

    Article  CAS  PubMed  Google Scholar 

  35. Zhu Z, Zhu S, Zhu J, van der Giet M, Tepel M . Endothelial dysfunction in cold-induced hypertensive rats. Am J Hypertens 2002; 15: 176–180.

    Article  CAS  PubMed  Google Scholar 

  36. Sun Z, Cade R . Cold-induced hypertension and diuresis. J Thermal Biol 2000; 25: 105–109.

    Article  CAS  Google Scholar 

  37. Sun Z, Cade R, Zhang Z, Alouidor J, Van H . Angiotensinogen gene knockout delays and attenuates cold-induced hypertension. Hypertension 2003; 41: 322–327.

    Article  CAS  PubMed  Google Scholar 

  38. Sun Z, Cade R, Tatum C . Central imidazoline and angiotensin II receptors in cardiovascular responses to chronic cold exposure in rats. J Therm Biol 2001; 26: 513–518.

    Article  CAS  Google Scholar 

  39. Sun Z, Cade R, Morales C . Role of central angiotensin II receptors in cold-induced hypertension. Am J Hypertens 2002; 15: 85–92.

    Article  CAS  PubMed  Google Scholar 

  40. Shechtman O, Fregly MJ, van Bergen P, Papanek PE . Prevention of cold-induced increase in blood pressure of rats by captopril. Hypertension 1991; 17: 763–770.

    Article  CAS  PubMed  Google Scholar 

  41. Sun Z, Fregly MJ, Rowland NE, Cade JR . Comparison of changes in blood pressure and dipsogenic responsiveness to angiotensin II in male and female rats chronically exposed to cold. Physiol Behav 1996; 60: 1543–1549.

    Article  CAS  PubMed  Google Scholar 

  42. Fregly MJ, Rossi F, Van Bergen P, Brummermann M, Cade JR . Effect of chronic treatment with losartan potassium (DuP 753) on the elevation of blood pressure during chronic exposure of rats to cold. Pharmacology 1993; 46: 198–205.

    Article  CAS  PubMed  Google Scholar 

  43. Pitard B, Bello-Roufai M, Lambert O, Richard P, Desigaux L, Fernandes S et al. Negatively charged self-assembling DNA/poloxamine nanospheres for in vivo gene transfer. Nucleic Acids Res 2004; 32: e159.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Zhong W, Mao S, Tobis S, Angelis E, Jordan MC, Roos KP et al. Hypertrophic growth in cardiac myocyte is mediated by Myc through a cyclin D2-dependent pathway. EMBO J 2006; 25: 3869–3879.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Fregly MJ, Rossi F, Sun Z, Tumer N, Cade JR, Hegland D et al. Effect of chronic treatment with prazosin and L-arginine on the elevation of blood pressure during cold exposure. Pharmacology 1994; 49: 351–362.

    Article  CAS  PubMed  Google Scholar 

  46. Fregly MJ, Rossi F, Cade R . A role for thyroid hormones in cold-induced elevation of blood pressure and cardiac hypertrophy. Can J Physiol Pharmacol 1994; 72: 1066–1074.

    Article  CAS  PubMed  Google Scholar 

  47. Kinugawa K, Jeong MY, Bristow MR, Long CS . Thyroid hormone induces cardiac myocyte hypertrophy in a thyroid hormone receptor alpha1-specific manner that requires TAK1 and p38 mitogen-activated protein kinase. Mol Endocrinol 2005; 19: 1618–1628.

    Article  CAS  PubMed  Google Scholar 

  48. Liang Q, Molkentin JD . Redefining the roles of p38 and JNK signalling in cardiac hypertrophy: dichotomy between cultured myocytes and animal models. J Mol Cell Cardiol 2005; 35: 1385–1394.

    Article  Google Scholar 

  49. Richard P, Bossard F, Desigaux L, Lanctin C, Bello-Roufai M, Pitard B . Amphiphilic block copolymers promote gene delivery in vivo to pathological skeletal muscles. Human Gene Ther 2005; 16: 1318–1324.

    Article  CAS  Google Scholar 

  50. Pitard B, Pollard H, Agbulut O, Lambert O, Vilquin JT, Cherel Y et al. A non-ionic amphiphile agent promotes gene delivery in vivo to skeletal and cardiac muscles. Human Gene Ther 2002; 13: 1767–1775.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by NIH R01 077490 (NHLBI). We thank Drs Jeffrey Robbins and Jim Gulick (University of Cincinnati, Cincinnati, USA) for providing us with α-MHC promoter.

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Authors and Affiliations

  1. Department of Physiology, College of Medicine, University of Oklahoma Health Science Center, Oklahoma City, OK, USA

    M Bello Roufai, H Li & Z Sun

  2. Departments of Medicine and Physiology & Functional Genomics, College of Medicine, University of Florida, Gainesville, FL, USA

    M Bello Roufai, H Li & Z Sun

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Correspondence to Z Sun.

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Bello Roufai, M., Li, H. & Sun, Z. Heart-specific inhibition of protooncogene c-myc attenuates cold-induced cardiac hypertrophy. Gene Ther 14, 1406–1416 (2007). https://doi.org/10.1038/sj.gt.3302995

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