(Circulation. 1999;99:22-25.)
© 1999 American Heart Association, Inc.
Brief Rapid Communications |
Angiotensin II Type 2 Receptor Blockade Amplifies the Early Signals of Cardiac Growth Response to Angiotensin II in Hypertrophied Hearts
From the Cardiovascular Division, The Harvard Thorndike Laboratory, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass.
Correspondence to Beverly H. Lorell, MD, Cardiovascular Division, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA 02215. E-mail blorell{at}bidmc.harvard.edu
Background—We have previously shown that the acute molecular growth response of new protein synthesis and protein kinase C activation in response to angiotensin II (Ang II) is altered in left ventricular (LV) hypertrophy compared with normal hearts. We have also shown an upregulation of Ang II type 2 (AT2) receptors in hypertrophied hearts relative to controls. Activation of AT2 receptors is proposed to counteract growth effects of AT1 receptor in response to Ang II. Thus, we tested the hypothesis that in hypertrophied hearts, the AT2 receptor mediates inhibitory effects on the new cardiac protein synthesis in response to acute Ang II stimulation.
Methods and Results—Flaccid buffer-perfused adult normal and hypertrophied rat hearts were perfused with Ang II 10-8 mol/L plus prazosin 10-7 mol/L or Ang II plus the AT2 blocker PD 123319 5x10-7 mol/L. New protein synthesis was measured by the rate of [3H]phenylalanine incorporation into the LV proteins. In normal hearts, Ang II (n=8) increased the rate of [3H]phenylalanine incorporation by 74±27% (P<0.05 versus no drug). Treatment with PD123319 (n=8) did not increase protein synthesis compared with Ang II alone (32±11% versus Ang II alone, P=NS). In hypertrophied hearts, Ang II alone (n=6) increased the rate of [3H]phenylalanine incorporation only by 23±13% (P=NS versus no drug). In contrast, treatment with PD123319 (n=7) induced a 76±21% increase in new LV protein synthesis compared with Ang II alone (P<0.05). AT2 receptor blockade in Ang II–stimulated hypertrophied hearts was associated with enhanced membrane protein kinase C translocation and reduced LV cGMP content.
Conclusions—These data support the hypothesis that in adult hypertrophied rat hearts, inhibition of cardiac AT2 receptors, which are upregulated in chronic LV hypertrophy, amplifies the immediate LV growth response to Ang II. This appears to be related to augmented Ang II–stimulated PKC activation and suppression of cGMP signaling.
Key Words: angiotensin • hypertrophy • signal transduction
This article has been cited by other articles:
 |
|
 |
|
  C. Warnecke, P. Mugrauer, D. Surder, J. Erdmann, C. Schubert, and V. Regitz-Zagrosek Intronic ANG II type 2 receptor gene polymorphism 1675 G/A modulates receptor protein expression but not mRNA splicing Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2005; 289(6): R1729 - R1735. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. J. Wruck, H. Funke-Kaiser, T. Pufe, H. Kusserow, M. Menk, J. H. Schefe, M. L. Kruse, M. Stoll, and T. Unger Regulation of Transport of the Angiotensin AT2 Receptor by a Novel Membrane-Associated Golgi Protein Arterioscler. Thromb. Vasc. Biol., January 1, 2005; 25(1): 57 - 64. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Johren, A. Dendorfer, and P. Dominiak Cardiovascular and renal function of angiotensin II type-2 receptors Cardiovasc Res, June 1, 2004; 62(3): 460 - 467. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Kumar, V. Menon, W. R. Ford, A. S. Clanachan, and B. I. Jugdutt Effect of Angiotensin II lype 2 Receptor Blockade on Activation of Mitogen-Activated Protein Kinases after Ischemia-Reperfusion in Isolated Working Rat Hearts Journal of Cardiovascular Pharmacology and Therapeutics, December 1, 2003; 8(4): 285 - 296. [Abstract] [PDF]
|
|
|
|
 |
|
 Z. Lako-Futo, I. Szokodi, B. Sarman, G. Foldes, H. Tokola, M. Ilves, H. Leskinen, O. Vuolteenaho, R. Skoumal, R. deChatel, et al. Evidence for a Functional Role of Angiotensin II Type 2 Receptor in the Cardiac Hypertrophic Process In Vivo in the Rat Heart Circulation, November 11, 2003; 108(19): 2414 - 2422. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Jones, S. S. Dhamrait, J. R. Payne, E. Hawe, P. Li, I. S. Toor, L. Luong, P. T.E. Wootton, G. J. Miller, S. E. Humphries, et al. Genetic Variants of Angiotensin II Receptors and Cardiovascular Risk in Hypertension Hypertension, October 1, 2003; 42(4): 500 - 506. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Kurisu, R. Ozono, T. Oshima, M. Kambe, T. Ishida, H. Sugino, H. Matsuura, K. Chayama, Y. Teranishi, O. Iba, et al. Cardiac Angiotensin II Type 2 Receptor Activates the Kinin/NO System and Inhibits Fibrosis Hypertension, January 1, 2003; 41(1): 99 - 107. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Yang, C. M. Bove, B. A. French, F. H. Epstein, S. S. Berr, J. M. DiMaria, J. J. Gibson, R. M. Carey, and C. M. Kramer Angiotensin II Type 2 Receptor Overexpression Preserves Left Ventricular Function After Myocardial Infarction Circulation, July 2, 2002; 106(1): 106 - 111. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Wu, M. Iwai, H. Nakagami, R. Chen, J. Suzuki, M. Akishita, M. de Gasparo, and M. Horiuchi Effect of Angiotensin II Type 1 Receptor Blockade on Cardiac Remodeling in Angiotensin II Type 2 Receptor Null Mice Arterioscler. Thromb. Vasc. Biol., January 1, 2002; 22(1): 49 - 54. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. L. Segar, G. B. Dalshaug, K. A. Bedell, O. M. Smith, and T. D. Scholz Angiotensin II in cardiac pressure-overload hypertrophy in fetal sheep Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2001; 281(6): R2037 - R2047. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Henrion, N. Kubis, and B. I. Levy Physiological and Pathophysiological Functions of the AT2 Subtype Receptor of Angiotensin II: From Large Arteries to the Microcirculation Hypertension, November 1, 2001; 38(5): 1150 - 1157. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. D. Schneider and B. H. Lorell AT2, Judgment Day: Which Angiotensin Receptor Is the Culprit in Cardiac Hypertrophy? Circulation, July 17, 2001; 104(3): 247 - 248. [Full Text] [PDF]
|
|
|
|
 |
|
 B. B. Roman, D. L. Geenen, M. Leitges, and P. M. Buttrick PKC-{beta} is not necessary for cardiac hypertrophy Am J Physiol Heart Circ Physiol, May 1, 2001; 280(5): H2264 - H2270. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. H. Opie and M. N. Sack Enhanced Angiotensin II Activity in Heart Failure : Reevaluation of the Counterregulatory Hypothesis of Receptor Subtypes Circ. Res., April 13, 2001; 88(7): 654 - 658. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. E. Schmieder, J. Erdmann, C. Delles, J. Jacobi, E. Fleck, K. Hilgers, and V. Regitz-Zagrosek Effect of the angiotensin II type 2-receptor gene (+1675 G/A) on left ventricular structure in humans J. Am. Coll. Cardiol., January 1, 2001; 37(1): 175 - 182. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Xu, A. S. Clanachan, and B. I. Jugdutt Enhanced Expression of Angiotensin II Type 2 Receptor, Inositol 1,4,5-Trisphosphate Receptor, and Protein Kinase C{epsilon} During Cardioprotection Induced by Angiotensin II Type 2 Receptor Blockade Hypertension, October 1, 2000; 36(4): 506 - 510. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Tamura, S. Said, J. Harris, W. Lu, and A. M. Gerdes Reverse Remodeling of Cardiac Myocyte Hypertrophy in Hypertension and Failure by Targeting of the Renin-Angiotensin System Circulation, July 11, 2000; 102(2): 253 - 259. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Elbaz, K. Bedecs, M. Masson, M. Sutren, A. D. Strosberg, and C. Nahmias Functional Trans-inactivation of Insulin Receptor Kinase by Growth-Inhibitory Angiotensin II AT2 Receptor Mol. Endocrinol., June 1, 2000; 14(6): 795 - 804. [Abstract] [Full Text]
|
|
|
|
 |
|
 Yi Xu, V. Menon, and B. I Jugdutt Cardioprotection after angiotensin II type 1 blockade involves angiotensin II type 2 receptor expression and activation of protein kinase C-{varepsilon} in acutely reperfused myocardial infarction in the dog: Effect of UP269-6 and losartan on AT1- and AT2-receptor expression and IP3 receptor and PKC{varepsilon} proteins Journal of Renin-Angiotensin-Aldosterone System, June 1, 2000; 1(2): 184 - 195. [Abstract] [PDF]
|
|
|
|
|
|
W. C. De Mello and A. H. J. Danser Angiotensin II and the Heart : On the Intracrine Renin-Angiotensin System Hypertension, June 1, 2000; 35(6): 1183 - 1188. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Gallinat, S. Busche, M. K. Raizada, and C. Sumners The angiotensin II type 2 receptor: an enigma with multiple variations Am J Physiol Endocrinol Metab, March 1, 2000; 278(3): E357 - E374. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. I. Jugdutt, Yi Xu, M. Balghith, R. Moudgil, and V. Menon Cardioprotection Induced by AT1R Blockade After Reperfused Myocardial Infarction: Association With Regional Increase in AT2R, IP3R and PKC{varepsilon} Proteins and cGMP Journal of Cardiovascular Pharmacology and Therapeutics, January 1, 2000; 5(4): 301 - 311. [Abstract] [PDF]
|
|
|
|
|
|
H. E. Cingolani Na+/H+ exchange hyperactivity and myocardial hypertrophy: Are they linked phenomena? Cardiovasc Res, December 1, 1999; 44(3): 462 - 467. [Full Text] [PDF]
|
|
|
|
|
|
S. Gunasegaram, R. S. Haworth, D. J. Hearse, and M. Avkiran Regulation of Sarcolemmal Na+/H+ Exchanger Activity by Angiotensin II in Adult Rat Ventricular Myocytes : Opposing Actions via AT1 Versus AT2 Receptors Circ. Res., November 12, 1999; 85(10): 919 - 930. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. C Wollert and H. Drexler The renin-angiotensin system and experimental heart failure Cardiovasc Res, September 1, 1999; 43(4): 838 - 849. [Abstract] [Full Text] [PDF]
|
|