Circulation Research, Vol 73, 413-423, Copyright © 1993 by American Heart Association

ARTICLES

Molecular characterization of angiotensin II--induced hypertrophy of cardiac myocytes and hyperplasia of cardiac fibroblasts. Critical role of the AT1 receptor subtype

J Sadoshima and S Izumo
Molecular Medicine Division, Beth Israel Hospital, Boston, Mass. 02215.

Increasing evidence suggests that angiotensin II (Ang II) may act as a growth factor for the heart. However, direct effects of Ang II on mammalian cardiac cells (myocytes and nonmyocytes), independent of secondary hemodynamic and neurohumoral effects, have not been well characterized. Therefore, we analyzed the molecular phenotype of cultured cardiac cells from neonatal rats in response to Ang II. In addition, we examined the effects of selective Ang II receptor subtype antagonists in mediating the biological effects of Ang II. In myocyte culture, Ang II caused an increase in protein synthesis without changing the rate of DNA synthesis. In contrast, Ang II induced increases in protein synthesis, DNA synthesis, and cell number in nonmyocyte cultures (mostly cardiac fibroblasts). The Ang II-induced hypertrophic response of myocytes and mitogenic response of fibroblasts were mediated primarily by the AT1 receptor. Ang II caused a rapid induction of many immediate-early genes (c-fos, c-jun, jun B, Egr-1, and c-myc) in myocyte and nonmyocyte cultures. Ang II induced "late" markers for cardiac hypertrophy, skeletal alpha-actin and atrial natriuretic factor expression, within 6 hours in myocytes. Ang II also caused upregulation of the angiotensinogen gene and transforming growth factor-beta 1 gene within 6 hours. Induction of immediate-early genes, late genes, and growth factor genes by Ang II was fully blocked by an AT1 receptor antagonist but not by an AT2 receptor antagonist. These results indicate that: (1) Ang II causes hypertrophy of cardiac myocytes and mitogenesis of cardiac fibroblasts, (2) the phenotypic changes of cardiac cells in response to Ang II in vitro closely mimic those of growth factor response in vitro and of load-induced hypertrophy in vivo, (3) all biological effects of Ang II examined here are mediated primarily by the AT1 receptor subtype, and (4) Ang II may initiate a positive-feedback regulation of cardiac hypertrophic response by inducing the angiotensinogen gene and transforming growth factor-beta 1 gene.

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				S. Y. Boateng, T. J. Hartman, N. Ahluwalia, H. Vidula, T. A. Desai, and B. Russell Inhibition of fibroblast proliferation in cardiac myocyte cultures by surface microtopography Am J Physiol Cell Physiol, July 1, 2003; 285(1): C171 - C182. [Abstract] [Full Text] [PDF]

				R. M. Carey and H. M. Siragy Newly Recognized Components of the Renin-Angiotensin System: Potential Roles in Cardiovascular and Renal Regulation Endocr. Rev., June 1, 2003; 24(3): 261 - 271. [Abstract] [Full Text] [PDF]

				J. Varagic, D. Susic, M. Slama, and E. D. Frohlich Omapatrilat Induces Profound Renal Vasodilation but Does Not Affect Coronary Hemodynamics Journal of Cardiovascular Pharmacology and Therapeutics, June 1, 2003; 8(2): 167 - 174. [Abstract] [PDF]

				D. J. Lips, L. J. deWindt, D. J.W. van Kraaij, and P. A. Doevendans Molecular determinants of myocardial hypertrophy and failure: alternative pathways for beneficial and maladaptive hypertrophy Eur. Heart J., May 2, 2003; 24(10): 883 - 896. [Abstract] [Full Text] [PDF]

				N C Sundgren, G D Giraud, P J S Stork, J G Maylie, and K L Thornburg Angiotensin II stimulates hyperplasia but not hypertrophy in immature ovine cardiomyocytes J. Physiol., May 1, 2003; 548(3): 881 - 891. [Abstract] [Full Text] [PDF]

				C. Rugale, S. Delbosc, J.-P. Cristol, A. Mimran, and B. Jover Sodium restriction prevents cardiac hypertrophy and oxidative stress in angiotensin II hypertension Am J Physiol Heart Circ Physiol, May 1, 2003; 284(5): H1744 - H1750. [Abstract] [Full Text] [PDF]

				K. Shivakumar, D. E. Dostal, K. Boheler, K. M. Baker, and E. G. Lakatta Differential response of cardiac fibroblasts from young adult and senescent rats to ANG II Am J Physiol Heart Circ Physiol, April 1, 2003; 284(4): H1454 - H1459. [Abstract] [Full Text] [PDF]

				M. Avkiran and R. S Haworth Regulatory effects of G protein-coupled receptors on cardiac sarcolemmal Na+/H+ exchanger activity: signalling and significance Cardiovasc Res, March 15, 2003; 57(4): 942 - 952. [Abstract] [Full Text] [PDF]

				K. Seta and J. Sadoshima Phosphorylation of Tyrosine 319 of the Angiotensin II Type 1 Receptor Mediates Angiotensin II-induced Trans-activation of the Epidermal Growth Factor Receptor J. Biol. Chem., March 7, 2003; 278(11): 9019 - 9026. [Abstract] [Full Text] [PDF]

				S. Der Sarkissian, E.-L. Marchand, D. Duguay, P. Hamet, and D. deBlois Reversal of interstitial fibroblast hyperplasia via apoptosis in hypertensive rat heart with valsartan or enalapril Cardiovasc Res, March 1, 2003; 57(3): 775 - 783. [Abstract] [Full Text] [PDF]

				A. C Rosenkranz, R. L Woods, G. J Dusting, and R. H Ritchie Antihypertrophic actions of the natriuretic peptides in adult rat cardiomyocytes: importance of cyclic GMP Cardiovasc Res, February 1, 2003; 57(2): 515 - 522. [Abstract] [Full Text] [PDF]

				H. El-Adawi, L. Deng, A. Tramontano, S. Smith, E. Mascareno, K. Ganguly, R. Castillo, and N. El-Sherif The functional role of the JAK-STAT pathway in post-infarction remodeling Cardiovasc Res, January 1, 2003; 57(1): 129 - 138. [Abstract] [Full Text] [PDF]

				S. Gupta, N. H. Purcell, A. Lin, and S. Sen Activation of nuclear factor-{kappa}B is necessary for myotrophin-induced cardiac hypertrophy J. Cell Biol., December 23, 2002; 159(6): 1019 - 1028. [Abstract] [Full Text] [PDF]

				I. Manabe, T. Shindo, and R. Nagai Gene Expression in Fibroblasts and Fibrosis: Involvement in Cardiac Hypertrophy Circ. Res., December 13, 2002; 91(12): 1103 - 1113. [Abstract] [Full Text] [PDF]

				R. Nakamura, J. Kato, K. Kitamura, H. Onitsuka, T. Imamura, K. Marutsuka, Y. Asada, K. Kangawa, and T. Eto Beneficial effects of adrenomedullin on left ventricular remodeling after myocardial infarction in rats Cardiovasc Res, December 1, 2002; 56(3): 373 - 380. [Abstract] [Full Text] [PDF]

				J. Agata, L. Chao, and J. Chao Kallikrein Gene Delivery Improves Cardiac Reserve and Attenuates Remodeling After Myocardial Infarction Hypertension, November 1, 2002; 40(5): 653 - 659. [Abstract] [Full Text] [PDF]

				M. R. Rosen The Electrocardiogram 100 Years Later: Electrical Insights Into Molecular Messages Circulation, October 22, 2002; 106(17): 2173 - 2179. [Full Text] [PDF]

				S. Ichihara, T. Senbonmatsu, E. Price Jr, T. Ichiki, F. A. Gaffney, and T. Inagami Targeted Deletion of Angiotensin II Type 2 Receptor Caused Cardiac Rupture After Acute Myocardial Infarction Circulation, October 22, 2002; 106(17): 2244 - 2249. [Abstract] [Full Text] [PDF]

				A. van der Laarse Hypothesis: troponin degradation is one of the factors responsible for deterioration of left ventricular function in heart failure Cardiovasc Res, October 1, 2002; 56(1): 8 - 14. [Abstract] [Full Text] [PDF]

				A. C. Rosenkranz, S. G. Hood, R. L. Woods, G. J. Dusting, and R. H. Ritchie Acute Antihypertrophic Actions of Bradykinin in the Rat Heart: Importance of Cyclic GMP Hypertension, October 1, 2002; 40(4): 498 - 503. [Abstract] [Full Text] [PDF]