Cyclic Nucleotide Phosphodiesterase 1 Regulates Lysosome-dependent Type I Collagen Protein Degradation in Vascular Smooth Muscle Cells

Overview

Journal Arterioscler Thromb Vasc Biol

Date 2010 Dec 15

PMID 21148428

Citations 18

Authors

Yujun Cai

Clint L Miller

David J Nagel

Kye-Im Jeon

Soyeon Lim

Pingjin Gao

Peter A Knight

Chen Yan

Affiliations

Soon will be listed here.

Abstract

Objective: The phenotypic modulation of vascular smooth muscle cells (VSMCs) to a synthetic phenotype is vital during pathological vascular remodeling and the development of various vascular diseases. An increase in type I collagen (collagen I) has been implicated in synthetic VSMCs, and cyclic nucleotide signaling is critical in collagen I regulation. Herein, we investigate the role and underlying mechanism of cyclic nucleotide phosphodiesterase 1 (PDE1) in regulating collagen I in synthetic VSMCs.

Methods And Results: The PDE1 inhibitor IC86340 significantly reduced collagen I in human saphenous vein explants undergoing spontaneous remodeling via ex vivo culture. In synthetic VSMCs, high basal levels of intracellular and extracellular collagen I protein were markedly decreased by IC86340. This attenuation was due to diminished protein but not mRNA. Inhibition of lysosome function abolished the effect of IC86340 on collagen I protein expression. PDE1C but not PDE1A is the major isoform responsible for mediating the effects of IC86340. Bicarbonate-sensitive soluble adenylyl cyclase/cAMP signaling was modulated by PDE1C, which is critical in collagen I degradation in VSMCs.

Conclusions: These data demonstrate that PDE1C regulates soluble adenylyl cyclase/cAMP signaling and lysosome-mediated collagen I protein degradation, and they suggest that PDE1C plays a critical role in regulating collagen homeostasis during pathological vascular remodeling.

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