Published online before print December 9, 2002, doi: 10.1161/01.CIR.0000043244.13596.20
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2003;107:106.)
© 2003 American Heart Association, Inc.
Basic Science Reports |
Fluvastatin Enhances the Inhibitory Effects of a Selective Angiotensin II Type 1 Receptor Blocker, Valsartan, on Vascular Neointimal Formation
From the Department of Medical Biochemistry, Ehime University School of Medicine, Ehime, Japan.
Correspondence to Masatsugu Horiuchi, MD, PhD, Department of Medical Biochemistry, Ehime University School of Medicine, Shigenobu, Onsen-gun, Ehime 791-0295, Japan. E-mail horiuchi{at}m.ehime-u.ac.jp
Background— The present studies were undertaken to investigate the potential effect of a hydroxymethylglutaryl coenzyme A reductase inhibitor (statin) to enhance the inhibitory effect of an angiotensin (Ang) II type 1 (AT1) receptor blocker (ARB) on vascular neointimal formation and to explore the cellular mechanism of cross-talk of the AT1 receptor and statin in vascular smooth muscle cells (VSMCs).
Methods and Results— Neointimal formation and the proliferation of VSMCs induced by cuff placement around the femoral artery were significantly inhibited by treatment with an ARB, valsartan, at a dose of 0.1 mg · kg-1 · d-1 and with fluvastatin at a dose of 1 mg · kg-1 · d-1, which did not influence mean arterial blood pressure or plasma cholesterol level, whereas valsartan or fluvastatin alone at these doses did not affect neointimal formation or the proliferation of VSMCs. Pretreatment with fluvastatin (
5 µmol/L) for 24 hours significantly inhibited Ang II (1 µmol/L)–mediated DNA synthesis and c-fos promoter activity in cultured VSMCs. Moreover, pretreatment of VSMCs with fluvastatin significantly inhibited Ang II–mediated extracellular signal-regulated kinase (ERK) activation and tyrosine- and serine-phosphorylation of signal transducer and activator of transcription (STAT)1 and STAT3. AT1 receptor–mediated recruitment of Rac-1 to Janus kinase (Jak) family/STATs was also inhibited by fluvastatin. Consistent with these in vitro results, phosphorylation of ERK, STAT1, and STAT3 was attenuated by the coadministration of valsartan and fluvastatin even at low doses in vivo.
Conclusion— These results suggest that the cholesterol-independent inhibition of AT1 receptor–mediated VSMC proliferation by statins may contribute to the beneficial effects of statins combined with an ARB on vascular diseases.
Key Words: angiotensin • hydroxymethylglutaryl coenzyme A reductase inhibitors • remodeling
This article has been cited by other articles:
 |
|
 |
|
  K. Ramasubbu, J. Estep, D. L. White, A. Deswal, and D. L. Mann Experimental and clinical basis for the use of statins in patients with ischemic and nonischemic cardiomyopathy. J. Am. Coll. Cardiol., January 29, 2008; 51(4): 415 - 426. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.-T. Tsai, L.-P. Lai, K.-T. Kuo, J.-J. Hwang, C.-S. Hsieh, K.-L. Hsu, C.-D. Tseng, Y.-Z. Tseng, F.-T. Chiang, and J.-L. Lin Angiotensin II Activates Signal Transducer and Activators of Transcription 3 via Rac1 in Atrial Myocytes and Fibroblasts: Implication for the Therapeutic Effect of Statin in Atrial Structural Remodeling Circulation, January 22, 2008; 117(3): 344 - 355. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Oshita, M. Iwai, R. Chen, A. Ide, M. Okumura, S. Fukunaga, T. Yoshii, M. Mogi, J. Higaki, and M. Horiuchi Attenuation of Inflammatory Vascular Remodeling by Angiotensin II Type 1 Receptor-Associated Protein Hypertension, October 1, 2006; 48(4): 671 - 676. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T.-M. Lee, M.-S. Lin, T.-F. Chou, and N.-C. Chang Additive effects of combined blockade of AT1 receptor and HMG-CoA reductase on left ventricular remodeling in infarcted rats Am J Physiol Heart Circ Physiol, September 1, 2006; 291(3): H1281 - H1289. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. van der Harst, A. A. Voors, W. H. van Gilst, M. Bohm, and D. J. van Veldhuisen Statins in the treatment of chronic heart failure: Biological and clinical considerations Cardiovasc Res, August 1, 2006; 71(3): 443 - 454. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. K. Banes-Berceli, S. Shaw, G. Ma, M. Brands, D. C. Eaton, D. M. Stern, D. Fulton, R. W. Caldwell, and M. B. Marrero Effect of simvastatin on high glucose- and angiotensin II-induced activation of the JAK/STAT pathway in mesangial cells Am J Physiol Renal Physiol, July 1, 2006; 291(1): F116 - F121. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Suzuki, M. Iwai, M. Mogi, A. Oshita, T. Yoshii, J. Higaki, and M. Horiuchi Eplerenone With Valsartan Effectively Reduces Atherosclerotic Lesion by Attenuation of Oxidative Stress and Inflammation Arterioscler. Thromb. Vasc. Biol., April 1, 2006; 26(4): 917 - 921. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. McMurray, S. Solomon, K. Pieper, S. Reed, J. Rouleau, E. Velazquez, H. White, J. Howlett, K. Swedberg, A. Maggioni, et al. The Effect of Valsartan, Captopril, or Both on Atherosclerotic Events After Acute Myocardial Infarction: An Analysis of the Valsartan in Acute Myocardial Infarction Trial (VALIANT) J. Am. Coll. Cardiol., February 21, 2006; 47(4): 726 - 733. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Iwai, R. Chen, Z. Li, T. Shiuchi, J. Suzuki, A. Ide, M. Tsuda, M. Okumura, L.-J. Min, M. Mogi, et al. Deletion of Angiotensin II Type 2 Receptor Exaggerated Atherosclerosis in Apolipoprotein E-Null Mice Circulation, September 13, 2005; 112(11): 1636 - 1643. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Arnaud, F. Burger, S. Steffens, N. R. Veillard, T. H. Nguyen, D. Trono, and F. Mach Statins Reduce Interleukin-6-Induced C-Reactive Protein in Human Hepatocytes: New Evidence for Direct Antiinflammatory Effects of Statins Arterioscler. Thromb. Vasc. Biol., June 1, 2005; 25(6): 1231 - 1236. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Sakamoto, T. Murata, H. Chuma, M. Hori, and H. Ozaki Fluvastatin Prevents Vascular Hyperplasia by Inhibiting Phenotype Modulation and Proliferation Through Extracellular Signal-Regulated Kinase 1 and 2 and p38 Mitogen-Activated Protein Kinase Inactivation in Organ-Cultured Artery Arterioscler. Thromb. Vasc. Biol., February 1, 2005; 25(2): 327 - 333. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. J. Park, K.-A. Ji, S.-B. Jeon, W.-H. Choi, I.-o. Han, H.-J. You, J.-H. Kim, I. Jou, and E.-H. Joe Rac1 Contributes to Maximal Activation of STAT1 and STAT3 in IFN-{gamma}-Stimulated Rat Astrocytes J. Immunol., November 1, 2004; 173(9): 5697 - 5703. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Li, M. Iwai, L. Wu, H.-W. Liu, R. Chen, T. Jinno, J. Suzuki, M. Tsuda, X.-Y. Gao, M. Okumura, et al. Fluvastatin Enhances the Inhibitory Effects of a Selective AT1 Receptor Blocker, Valsartan, on Atherosclerosis Hypertension, November 1, 2004; 44(5): 758 - 763. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Nickenig Should Angiotensin II Receptor Blockers and Statins Be Combined? Circulation, August 24, 2004; 110(8): 1013 - 1020. [Full Text] [PDF]
|
|
|
|
|
|
F. Cipollone, M. Fazia, A. Iezzi, B. Pini, C. Cuccurullo, M. Zucchelli, D. de Cesare, S. Ucchino, F. Spigonardo, M. De Luca, et al. Blockade of the Angiotensin II Type 1 Receptor Stabilizes Atherosclerotic Plaques in Humans by Inhibiting Prostaglandin E2-Dependent Matrix Metalloproteinase Activity Circulation, March 30, 2004; 109(12): 1482 - 1488. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Jinno, M. Iwai, Z. Li, J.-M. Li, H.-W. Liu, T.-X. Cui, H. Rakugi, T. Ogihara, and M. Horiuchi Calcium Channel Blocker Azelnidipine Enhances Vascular Protective Effects of AT1 Receptor Blocker Olmesartan Hypertension, February 1, 2004; 43(2): 263 - 269. [Abstract] [Full Text] [PDF]
|
|