on June 25, 2007
Published online before print June 25, 2007, doi: 10.1161/HYPERTENSIONAHA.107.091264
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on April 11, 2007
From the Vascular and Renal Research Laboratory, Cellular Biology in Renal Diseases Laboratory, Fundación Jiménez Diaz, Universidad Autónoma Madrid, Spain. * To whom correspondence should be addressed. E-mail: mruizo{at}fjd.es.
Abstract--3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase inhibitors (statins) present beneficial effects in cardiovascular diseases. Angiotensin II (Ang II) contributes to cardiovascular damage through the production of profibrotic factors, such as connective tissue growth factor (CTGF). Our aim was to investigate whether HMG-CoA reductase inhibitors could modulate Ang II responses, evaluating CTGF expression and the mechanisms underlying this process. In cultured vascular smooth muscle cells (VSMCs) atorvastatin and simvastatin inhibited Ang II-induced CTGF production. The inhibitory effect of statins on CTGF upregulation was reversed by mevalonate and geranylgeranylpyrophosphate, suggesting that RhoA inhibition could be involved in this process. In VSMCs, statins inhibited Ang II-induced Rho membrane localization and activation. In these cells Ang II regulated CTGF via RhoA/Rho kinase activation, as shown by inhibition of Rho with C3 exoenzyme, RhoA dominant-negative overexpression, and Rho kinase inhibition. Furthermore, activation of p38MAPK and JNK, and redox process were also involved in Ang II-mediated CTGF upregulation, and were downregulated by statins. In rats infused with Ang II (100 ng/kg/min) for 2 weeks, treatment with atorvastatin (5 mg/Kg/d) diminished aortic CTGF and Rho activation without blood pressure modification. Rho kinase inhibition decreased CTGF upregulation in rat aorta, mimicking statin effect. CTGF is a vascular fibrosis mediator. Statins diminished extracellular matrix (ECM) overexpression caused by Ang II in vivo and in vitro. In summary, HMG-CoA reductase inhibitors inhibit several intracellular signaling systems activated by Ang II (RhoA/Rho kinase and MAPK pathways and redox process) involved in the regulation of CTGF. Our results may explain, at least in part, some beneficial effects of statins in cardiovascular diseases.
Revised on April 29, 2007
HMG-CoA Reductase Inhibitors Decrease Angiotensin II-Induced Vascular Fibrosis. Role of RhoA/ROCK and MAPK Pathways
Mónica Rupérez;
Key words: angiotensin • RhoA • Rho kinase • extracellular matrix • HMG CoA reductase • vascular smooth muscle cells
This article has been cited by other articles:
 |
|
 |
|
  S.-A Chang, Y.-J. Kim, H.-W. Lee, D.-H. Kim, H.-K. Kim, H.-J. Chang, D.-W. Sohn, B.-H. Oh, and Y.-B. Park Effect of Rosuvastatin on Cardiac Remodeling, Function, and Progression to Heart Failure in Hypertensive Heart With Established Left Ventricular Hypertrophy Hypertension, September 1, 2009; 54(3): 591 - 597. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Briones, N. Rodriguez-Criado, R. Hernanz, A. B. Garcia-Redondo, R. R. Rodrigues-Diez, M. J. Alonso, J. Egido, M. Ruiz-Ortega, and M. Salaices Atorvastatin Prevents Angiotensin II-Induced Vascular Remodeling and Oxidative Stress Hypertension, July 1, 2009; 54(1): 142 - 149. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Jarvelainen, A. Sainio, M. Koulu, T. N. Wight, and R. Penttinen Extracellular Matrix Molecules: Potential Targets in Pharmacotherapy Pharmacol. Rev., June 1, 2009; 61(2): 198 - 223. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Moreno, L. N. Ramalho, P. Sancho-Bru, M. Ruiz-Ortega, F. Ramalho, J. G. Abraldes, J. Colmenero, M. Dominguez, J. Egido, V. Arroyo, et al. Atorvastatin attenuates angiotensin II-induced inflammatory actions in the liver Am J Physiol Gastrointest Liver Physiol, February 1, 2009; 296(2): G147 - G156. [Abstract] [Full Text] [PDF]
|
|