title: Cyclic nucleotide phosphodiesterase 1 regulates lysosome-dependent type I collagen protein degradation in vascular smooth muscle cells.
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.
  
  
  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.
authors.affiliation: Aab Cardiovascular Research Institute, University of Rochester, Rochester, NY 14642, USA.
authors.forename: Yujun
authors.initials: Y
authors.lastname: Cai
authors.forename: Clint L
authors.initials: CL
authors.lastname: Miller
authors.forename: David J
authors.initials: DJ
authors.lastname: Nagel
authors.forename: Kye-Im
authors.initials: KI
authors.lastname: Jeon
authors.forename: Soyeon
authors.initials: S
authors.lastname: Lim
authors.forename: Pingjin
authors.initials: P
authors.lastname: Gao
authors.forename: Peter A
authors.initials: PA
authors.lastname: Knight
authors.forename: Chen
authors.initials: C
authors.lastname: Yan
mesh_terms: D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001639:Bicarbonates / Q000378:metabolism; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000187:drug effects / Q000201:enzymology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology*; D010641:Phenotype; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D051381:Rats; D015398:Signal Transduction; D046509:Tissue Culture Techniques
chemical_list: D001639:Bicarbonates; D024042:Collagen Type I; D054815:Cyclic Nucleotide-Gated Cation Channels; D020662:Guanine Nucleotide Exchange Factors; D010726:Phosphodiesterase Inhibitors; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D017869:Cyclic GMP-Dependent Protein Kinases; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; C517274:Pde1C protein, rat; C517263:Pde1a protein, rat; D000262:Adenylyl Cyclases