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. 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. Conclusion 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.

Cyclic nucleotide phosphodiesterase 1A: a key regulator of cardiac fibroblast activation and extracellular matrix remodeling in the heart

“…The specificity of the PDE1A and PDE1C shRNA on PDE1A and PDE1C expression was demonstrated in Fig. S3e–g, consistent with previous findings in rat cardiomyocytes [38] and vascular smooth muscle cells (VSMCs) [11]. These results suggest that the effects of IC86340 on ECM synthesis in cardiac fibroblasts are primarily mediated by PDE1A.…”

“…The degradation of structural collagen may also lead to systolic or diastolic dysfunction [28]. We recently demonstrated PDE1C but not PDE1A regulates lysosomal-dependent degradation of the basal type I collagen in VSMCs [11]. Herein we show that PDE1A regulates agonist stimulated collagen synthesis through changes in gene expression, suggesting two distinct mechanisms of collagen homeostasis regulated by different PDE1 isozymes.…”

“…Adenovirus vectors encoding PDE1A and LacZ shRNA were constructed using BLOCK-iT Adenoviral shRNA Expression System (Invitrogen) according to the manufacturer’s instructions as described previously [11]. …”

PDE1C deficiency antagonizes pathological cardiac remodeling and dysfunction

“…Nevertheless, the generation of mice with cardiac myocyte-specific depletion of PDE1C in the future will be helpful. Although PDE1C hydrolyzes both cAMP and cGMP with high affinity in cell-free conditions (16), most cellular studies to date have shown that PDE1C regulates cAMP signaling primarily in cells such as proliferating vascular smooth muscle cells (23,34) and pancreatic B cells (35). In this study we also demonstrated that PDE1C regulates cAMP levels, particularly Ang II-mediated suppression of cAMP ( Fig.…”

Vinpocetine Suppresses Pathological Vascular Remodeling by Inhibiting Vascular Smooth Muscle Cell Proliferation and Migration

“…This leads to an increased thickness of the SV vessel wall. The SV wall can be divided into three zones, the internal zone (intima), the medial zone (inner and outer media), and the external zone (inner and outer adventitia) (Cai et al, 2011). With Verhoeff Masson trichrome combination staining, smooth muscles are stained with red, collagen with light blue or blue-green, and elastin with dark blue (Fig.…”