Published Online
on October 4, 2004

A more recent version of this article appeared on November 1, 2004

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Submitted on June 10, 2004
Revised on June 28, 2004

Angiotensin II Regulation of Collagen Type I Expression in Cardiac Fibroblasts. Modulation by PPAR- Ligand Pioglitazone

Kui Chen; Jiawei Chen; Dayuan Li; Xingjian Zhang; and Jawahar L. Mehta^*

From the Departments of Internal Medicine and Physiology and Biophysics, University of Arkansas for Medical Sciences, and the Central Arkansas Veterans Healthcare System, Little Rock.

^* To whom correspondence should be addressed. E-mail: MehtaJL{at}uams.edu.

Abstract--Angiotensin II (Ang II)-mediated stimulation of fibroblast growth and collagen type I synthesis is believed to be an important component of the cardiac remodeling process in hypertension and chronic ischemia. Ang II-mediated oxidative stress could be important in enhanced fibroblast growth and collagen formation. Accordingly, we postulated that the PPAR- ligand, pioglitazone, which is known to modulate oxidative stress, would alter Ang II-induced formation of collagen type I in cardiac fibroblasts. Cardiac fibroblasts were treated with different concentrations (10^-8 to 10^-6 M) of Ang II for different times (6 hours, 12 hours, and 24 hours). Ang II increased the expression of collagen type I in a concentration- and time-dependent fashion (P<0.01 versus control). Ang II also decreased the expression and activity of matrix metalloproteinase (MMP)-1 (MMP-1, P<0.05 versus control). These effects of Ang II were attenuated by pretreatment of cells with pioglitazone (10 µmol/L). Ang II stimulated the intracellular generation of reactive oxygen species (ROS), and this effect was also attenuated by pioglitazone. Ang II treatment activated the redox-sensitive transcription factor NF-B, and pioglitazone pretreatment blocked this effect of Ang II. Ang II also activated another transcription factor, AP-1, but this effect of Ang II was not modulated by pioglitazone. In other experiments, we observed that trolox, the water soluble analog of vitamin E, attenuated the effects of Ang II on the expression of collagen type I and MMP-1, in a manner similar to pioglitazone. Thus, pioglitazone attenuates Ang II-mediated collagen type I synthesis in cardiac fibroblasts. The effects of pioglitazone are mediated by the modulation of ROS release and redox-sensitive transcription factor NF-B.

Key words: angiotensin II • cardiac function • collagen

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