© 2001 American Heart Association, Inc.
Cellular Biology |
Canine Ventricular Myocytes Possess a Renin-Angiotensin System That Is Upregulated With Heart Failure
From the Departments of Medicine (L.B., A.L., F.F., J.K., B.N.-G., P.A.) and Physiology (H.T., T.H.H.), New York Medical College, Valhalla, NY; Division of Molecular Cardiology (D.E.D.), The Texas A&M University, Temple, Tex; and Istituto Ricerche Farmacologiche Mario Negri (F.F.), Milano, Italy.
Correspondence to Piero Anversa, MD, Department of Medicine, Vosburgh Pavilion, Room 302, New York Medical College, Valhalla, NY 10595. E-mail piero_anversa{at}nymc.edu
Abstract—Ventricular pacing leads to a dilated myopathy in which cell death and myocyte hypertrophy predominate. Because angiotensin II (Ang II) stimulates myocyte growth and triggers apoptosis, we tested whether canine myocytes express the components of the renin-angiotensin system (RAS) and whether the local RAS is upregulated with heart failure. p53 modulates transcription of angiotensinogen (Aogen) and AT1 receptors in myocytes, raising the possibility that enhanced p53 function in the decompensated heart potentiates Ang II synthesis and Ang II–mediated responses. Therefore, the presence of mRNA transcripts for Aogen, renin, angiotensin-converting enzyme, chymase, and AT1 and AT2 receptors was evaluated by reverse transcriptase–polymerase chain reaction in myocytes. Changes in the protein expression of these genes were then determined by Western blot in myocytes from control dogs and dogs affected by congestive heart failure. p53 binding to the promoter of Aogen and AT1 receptor was also determined. Ang II in myocytes was measured by ELISA and by immunocytochemistry and confocal microscopy. Myocytes expressed mRNAs for all the constituents of RAS, and heart failure was characterized by increased p53 DNA binding to Aogen and AT1. Additionally, protein levels of Aogen, renin, cathepsin D, angiotensin-converting enzyme, and AT1 were markedly increased in paced myocytes. Conversely, chymase and AT2 proteins were not altered. Ang II quantity and labeling of myocytes increased significantly with cardiac decompensation. In conclusion, dog myocytes synthesize Ang II, and activation of p53 function with ventricular pacing upregulates the myocyte RAS and the generation and secretion of Ang II. Ang II may promote myocyte growth and death, contributing to the development of heart failure.
Key Words: pacing • myocyte renin-angiotensin system • p53 function • heart failure
This article has been cited by other articles:
 |
|
 |
|
  A. Whaley-Connell, J. Habibi, S. A. Cooper, V. G. DeMarco, M. R. Hayden, C. S. Stump, D. Link, C. M. Ferrario, and J. R. Sowers Effect of renin inhibition and AT1R blockade on myocardial remodeling in the transgenic Ren2 rat Am J Physiol Endocrinol Metab, July 1, 2008; 295(1): E103 - E109. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. P. Singh, K. M. Baker, and R. Kumar Activation of the intracellular renin-angiotensin system in cardiac fibroblasts by high glucose: role in extracellular matrix production Am J Physiol Heart Circ Physiol, April 1, 2008; 294(4): H1675 - H1684. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Murtaza, H.-X. Wang, X. Feng, N. Alenina, M. Bader, B. S. Prabhakar, and P.-F. Li Down-regulation of Catalase and Oxidative Modification of Protein Kinase CK2 Lead to the Failure of Apoptosis Repressor with Caspase Recruitment Domain to Inhibit Cardiomyocyte Hypertrophy J. Biol. Chem., March 7, 2008; 283(10): 5996 - 6004. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Burstein and S. Nattel Atrial Fibrosis: Mechanisms and Clinical Relevance in Atrial Fibrillation J. Am. Coll. Cardiol., February 26, 2008; 51(8): 802 - 809. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-Z. Li, D.-Y. Lu, W.-Q. Tan, J.-X. Wang, and P.-F. Li p53 Initiates Apoptosis by Transcriptionally Targeting the Antiapoptotic Protein ARC Mol. Cell. Biol., January 15, 2008; 28(2): 564 - 574. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Burstein, X.-Y. Qi, Y.-H. Yeh, A. Calderone, and S. Nattel Atrial cardiomyocyte tachycardia alters cardiac fibroblast function: A novel consideration in atrial remodeling Cardiovasc Res, December 1, 2007; 76(3): 442 - 452. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. A. Cooper, A. Whaley-Connell, J. Habibi, Y. Wei, G. Lastra, C. Manrique, S. Stas, and J. R. Sowers Renin-angiotensin-aldosterone system and oxidative stress in cardiovascular insulin resistance Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2009 - H2023. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. P. Singh, B. Le, V. B. Bhat, K. M. Baker, and R. Kumar High-glucose-induced regulation of intracellular ANG II synthesis and nuclear redistribution in cardiac myocytes Am J Physiol Heart Circ Physiol, August 1, 2007; 293(2): H939 - H948. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Whaley-Connell, G. Govindarajan, J. Habibi, M. R. Hayden, S. A. Cooper, Y. Wei, L. Ma, M. Qazi, D. Link, P. R. Karuparthi, et al. Angiotensin II-mediated oxidative stress promotes myocardial tissue remodeling in the transgenic (mRen2) 27 Ren2 rat Am J Physiol Endocrinol Metab, July 1, 2007; 293(1): E355 - E363. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.-P. Cheng, H.-J. Cheng, C. Cunningham, Z. K. Shihabi, D. C. Sane, T. Wannenburg, and W. C. Little Angiotensin II Type 1 Receptor Blockade Prevents Alcoholic Cardiomyopathy Circulation, July 18, 2006; 114(3): 226 - 236. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Modesti, I. Bertolozzi, T. Gamberi, M. Marchetta, C. Lumachi, M. Coppo, F. Moroni, T. Toscano, G. Lucchese, G. F. Gensini, et al. Hyperglycemia Activates JAK2 Signaling Pathway in Human Failing Myocytes via Angiotensin II-Mediated Oxidative Stress Diabetes, February 1, 2005; 54(2): 394 - 401. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Funabiki, K. Onishi, K. Dohi, T. Koji, K. Imanaka-Yoshida, M. Ito, H. Wada, N. Isaka, T. Nobori, and T. Nakano Combined angiotensin receptor blocker and ACE inhibitor on myocardial fibrosis and left ventricular stiffness in dogs with heart failure Am J Physiol Heart Circ Physiol, December 1, 2004; 287(6): H2487 - H2492. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Rondelet, F. Kerbaul, R. Van Beneden, S. Motte, P. Fesler, I. Hubloue, M. Remmelink, S. Brimioulle, I. Salmon, J.-M. Ketelslegers, et al. Signaling Molecules in Overcirculation-Induced Pulmonary Hypertension in Piglets: Effects of Sildenafil Therapy Circulation, October 12, 2004; 110(15): 2220 - 2225. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. B. Silver, A. C. Reid, C. J. Mackins, T. Askwith, U. Schaefer, D. Herzlinger, and R. Levi Mast cells: A unique source of renin PNAS, September 14, 2004; 101(37): 13607 - 13612. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Shimoni and X.-F. Liu Gender differences in ANG II levels and action on multiple K+ current modulation pathways in diabetic rats Am J Physiol Heart Circ Physiol, July 1, 2004; 287(1): H311 - H319. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Nakajima, H. O. Nakajima, S.-C. Tsai, and L. J. Field Expression of Mutant p193 and p53 Permits Cardiomyocyte Cell Cycle Reentry After Myocardial Infarction in Transgenic Mice Circ. Res., June 25, 2004; 94(12): 1606 - 1614. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Unger and Jun Li The role of the renin-angiotensin-aldosterone system in heart failure Journal of Renin-Angiotensin-Aldosterone System, March 1, 2004; 5(1_suppl): S7 - S10. [Abstract] [PDF]
|
|
|
|
 |
|
 A. Stanton, C. Jensen, J. Nussberger, and E. O'Brien Blood Pressure Lowering in Essential Hypertension With an Oral Renin Inhibitor, Aliskiren Hypertension, December 1, 2003; 42(6): 1137 - 1143. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Cardin, D. Li, N. Thorin-Trescases, T.-K. Leung, E. Thorin, and S. Nattel Evolution of the atrial fibrillation substrate in experimental congestive heart failure: angiotensin-dependent and -independent pathways Cardiovasc Res, November 1, 2003; 60(2): 315 - 325. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. N. Re Intracellular Renin and the Nature of Intracrine Enzymes Hypertension, August 1, 2003; 42(2): 117 - 122. [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]
|
|
|
|
 |
|
 A. J. Casal, J.-S. Silvestre, C. Delcayre, and A. M. Capponi Expression and Modulation of Steroidogenic Acute Regulatory Protein Messenger Ribonucleic Acid in Rat Cardiocytes and after Myocardial Infarction Endocrinology, May 1, 2003; 144(5): 1861 - 1868. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Stanton Review: Potential of renin inhibition in cardiovascular disease Journal of Renin-Angiotensin-Aldosterone System, March 1, 2003; 4(1): 6 - 10. [Abstract] [PDF]
|
|
|
|
|
|
J. M. Wang, D. Slembrouck, J. Tan, L. Arckens, F. H. H. Leenen, P. J. Courtoy, and W. P. De Potter Presence of cellular renin-angiotensin system in chromaffin cells of bovine adrenal medulla Am J Physiol Heart Circ Physiol, November 1, 2002; 283(5): H1811 - H1818. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. R. Freshour, S. E. Chase, and K. L. Vikstrom Gender differences in cardiac ACE expression are normalized in androgen-deprived male mice Am J Physiol Heart Circ Physiol, November 1, 2002; 283(5): H1997 - H2003. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. S. Pachori, M. T. Numan, C. M. Ferrario, D. M. Diz, M. K. Raizada, and M. J. Katovich Blood Pressure-Independent Attenuation of Cardiac Hypertrophy by AT1R-AS Gene Therapy Hypertension, May 1, 2002; 39(5): 969 - 975. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. N. Re On Not Being the Last to Give Up the Old or the First to Adopt the New Hypertension, October 1, 2001; 38(4): 759 - 760. [Full Text] [PDF]
|
|
|
|
|
|
A. Leri, L. Barlucchi, F. Limana, A. Deptala, Z. Darzynkiewicz, T. H. Hintze, J. Kajstura, B. Nadal-Ginard, and P. Anversa Telomerase expression and activity are coupled with myocyte proliferation and preservation of telomeric length in the failing heart PNAS, July 5, 2001; (2001) 151013298. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Leri, L. Barlucchi, F. Limana, A. Deptala, Z. Darzynkiewicz, T. H. Hintze, J. Kajstura, B. Nadal-Ginard, and P. Anversa Telomerase expression and activity are coupled with myocyte proliferation and preservation of telomeric length in the failing heart PNAS, July 17, 2001; 98(15): 8626 - 8631. [Abstract] [Full Text] [PDF]
|
|