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J. Biol. Chem., Vol. 283, Issue 16, 10226-10231, April 18, 2008

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Regulation of TGFβ₁-mediated Collagen Formation by LOX-1

Studies Based on Forced Overexpression of TGFβ₁ in Wild-Type and Lox-1^*

Changping Hu¹, Abhijit Dandapat¹, Liuqin Sun^¶, Junaid A. Khan, Yong Liu, Paul L. Hermonat, and Jawahar L. Mehta²

From the Cardiovascular Medicine, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, Arkansas 72205-7199, Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha 410078 China, and ^¶Department of Ophthalmology, Heping Hospital, Changzhi Medical College, Changzhi 046000 China

Transforming growth factor β₁ (TGFβ₁) activation leads to tissue fibrosis. Here, we report on the role of LOX-1, a lectin-like 52-kDa receptor for oxidized low density lipoprotein, in TGFβ₁-mediated collagen expression and underlying signaling in mouse cardiac fibroblasts. TGFβ₁ was overexpressed in wild-type (WT) and LOX-1 knock-out mouse cardiac fibroblasts by transfection with adeno-associated virus type 2 vector carrying the active TGFβ₁ moiety (AAV/TGFβ ^ACT₁). Transfection of WT mouse cardiac fibroblasts with AAV/TGFβ ^ACT₁ markedly enhanced the expression of NADPH oxidases (p22^phox, p47^phox, and gp91^phox subunits) and LOX-1, formation of reactive oxygen species, and collagen synthesis, concomitant with an increase in the activation of p38 and p44/42 mitogen-activated protein kinases (MAPK). The TGFβ₁-mediated increase in collagen synthesis was markedly attenuated in the LOX-1 knock-out mouse cardiac fibroblasts as well as in WT mouse cardiac fibroblasts treated with a specific anti-LOX-1 antibody. Treatment with anti-LOX-1 antibody also reduced NADPH oxidase expression and MAPK activation. The NADPH oxidase inhibitors and gp91phox small interfering RNA reduced LOX-1 expression, MAPK activation, and collagen formation. The p38 MAPK inhibitors as well as the p44/42 MAPK inhibitors reduced collagen formation without affecting LOX-1 expression in cardiac fibroblasts. These observations suggest that collagen synthesis in cardiac fibroblasts involves a facilitative interaction between TGFβ₁-NADPH oxidase and LOX-1. Further, the activation of MAPK pathway appears to be downstream of TGFβ₁-reactive oxygen species-LOX-1 cascade.

Received for publication, October 25, 2007 , and in revised form, December 26, 2007.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: UAMS, Little Rock, AR 72205. E-mail: mehtaJL{at}uams.edu.

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