Phosphodiesterase 3 and Atherosclerosis

University Of Rochester, Rochester NY

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Abstract

The progression of atherosclerotic lesions is believed to be a chronic inflammatory process involving vascular[unreadable] remodeling of the vessel wall. There is increasing evidence that direct pathobiological events in the vessel wall play[unreadable] an important role in atherosclerosis. Vascular endothelial cell (EC) and smooth muscle cell (VSMC) are both[unreadable] important targets for inflammatory cytokines and also capable of producing significant amounts of cytokines,[unreadable] chemokines, and adhesion molecules. The development of atherosclerosis may involve the perturbation of the[unreadable] homeostatic balance between the anti-atherosclerotic signaling (such as nitric oxide (NO), C-type natriuretic[unreadable] peptide (CNP), and cyclic nucleotides) and the pro-atherosclerotic signaling (such as TNF alpha and Ang II).[unreadable] Cyclic nucleotide phosphodiesterases (PDEs) play critical roles in regulating intracellular cyclic nucleotide (cAMP[unreadable] and cGMP) levels and compartmentalization via degradation of cyclic nucleotides. We have recently shown that[unreadable] NO and CNP inhibited NF-kappaB-dependent inflammatory molecule expression in cultured VSMCs via a[unreadable] cGMP-dependent inhibition of phosphodiesterase 3 (PDE3). PDE3 is the major cAMP-hydrolyzing PDE present[unreadable] in VSMC and its inhibition by NO-cGMP and CNP-cGMP results in increased PKA activity, which inhibits[unreadable] NF-kappaB activation and inflammatory molecule expression. Furthermore inhibition of PDE3 function[unreadable] specifically blocked TNFalpha-stimulated NF-kappaB activation and inflammatory molecule expression. These[unreadable] results suggest that PDE3 activity is a critical regulator of inflammatory gene expression in VSMC and that[unreadable] cGMP-mediated inhibition of PDE3 activity is the mechanism of the anti-inflammatory effects of NO-cGMP and[unreadable] CNP-cGMP in VSMC. To determine the role of PDE3 in the regulation of VSMC inflammatory molecule[unreadable] expression and atherosclerosis formation, we propose the following three aims: Aim 1: Identify the specific isoform[unreadable] of PDE3 involved in regulating NF-kappaB-dependent inflammatory molecule expression in VSMC in vitro. Aim[unreadable] 2: Determine the role of PDE3 in the regulation of inflammatory molecule expression in VSMC in ex vivo cultured[unreadable] vessels using the organ culture system. Aim 3: Determine the effect of VSMC overexpression of a PDE3 isoform[unreadable] on atherosclerosis using genetically modified mice.