Phosphodiesterase 3 and Atherosclerosis

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