The PDE1A-PKCalpha Signaling Pathway is Involved in the Upregulation of Alpha-smooth Muscle Actin by TGF-beta1 in Adventitial Fibroblasts

Overview

Journal J Vasc Res

Specialty Cardiology & Vascular Diseases

Date 2009 Aug 13

PMID 19672103

Citations 18

Authors

Hai-Yan Zhou

Wen-Dong Chen

Ding-Liang Zhu

Ling-Yun Wu

Jia Zhang

Wei-Qing Han

Jian-Dong Li

Chen Yan

Ping-Jin Gao

Affiliations

Soon will be listed here.

Abstract

Background: Increasing evidence has suggested that differentiation of adventitial fibroblasts (AFs) to myofibroblasts plays an important role in arterial remodeling. The molecular mechanisms by which myofibroblast formation is regulated still remain largely unknown. This study aimed to evaluate the role of cyclic nucleotide phosphodiesterase 1A (PDE1A) in the formation of adventitial myofibroblasts induced by transforming growth factor (TGF)-beta(1).

Methods And Results: AFs were cultured by the explant method. Western blot and immunocytochemistry were applied for alpha-smooth muscle actin (SMA) or protein kinase C (PKC) alpha protein analysis. Results showed that TGF-beta(1) upregulated PDE1A protein expression in rat aortic AFs and pharmacological inhibition of PDE1A blocked TGF-beta(1)-induced alpha-SMA expression, a marker of myofibroblast formation, suggesting that the upregulation of PDE1A may mediate TGF-beta(1)-induced AF transformation. Moreover, calphostin C (a PKC inhibitor) inhibited TGF-beta(1)-induced alpha-SMA expression, whereas phorbol-12-myristate-13-acetate (a PKC activator) induced it. Finally, the upregulation of PKCalpha expression by TGF-beta(1) was also inhibited by PDE1A inhibition.

Conclusions: Taken together, our data suggest that TGFbeta(1) induces alpha-SMA expression and myofibroblast formation via a PDE1A-PKCalpha-dependent mechanism. Our study thus unveils a novel signaling mechanism underlying TGF-beta(1)-induced adventitial myofibroblast formation.

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