Adenylyl Cyclase 3 Mediates Prostaglandin E2-induced Growth Inhibition in Arterial Smooth Muscle Cells

Abstract

Arterial smooth muscle cell (SMC) proliferation contributes to a number of vascular pathologies. Prostaglandin E 2 (PGE 2 ), produced by the endothelium and by SMCs themselves, acts as a potent SMC growth inhibitor. The growth-inhibitory effects of PGE 2 are mediated through activation of G-protein-coupled membrane receptors, activation of adenylyl cyclases (ACs), formation of cAMP, and subsequent inhibition of mitogenic signal transduction pathways in SMCs. Of the 10 different mammalian AC isoforms known today, seven isoforms (AC2-7 and AC9) are expressed in SMCs from various species. We show that, despite the presence of several different AC isoforms, the principal AC isoform activated by PGE 2 in human arterial SMCs is a calmodulin kinase II-inhibited AC with characteristics similar to those of AC3. AC3 is expressed in isolated human arterial SMCs and in intact aorta. We further show that arterial SMCs isolated from AC3-deficient mice are resistant to PGE 2 -induced growth inhibition. In summary, AC3 is the principal AC isoform activated by PGE 2 in arterial SMCs, and AC3 mediates the growth-inhibitory effects of PGE 2 . Because AC3 activity is inhibited by intracellular calcium through calmodulin kinase II, AC3 may serve as an important integrator of growth-inhibitory signals that stimulate cAMP formation and growth factors that increase intracellular calcium.

Long Lasting Inhibition of Adenylyl Cyclase Selectively Mediated by Inositol 1,4,5-Trisphosphate-evoked Calcium Release

“…9A) signal. Previous work with arterial smooth muscle established that although it expressed several AC isoforms, prostaglandin E 2 stimulated only AC-3 and that such stimulation was essential for inhibition of cell proliferation (27). This result highlights the likely importance of AC-3 in vascular smooth muscle, and its involvement in controlling a long-term response provides a satisfying link with our observation that transient Ca (100 nM, E, open bar).…”

“…In smooth muscle, such interactions are major determinants of both contractile activity and proliferation (27). Ca 2ϩ promotes contraction by stimulating phosphorylation of myosin light chain, whereas cGMP and cAMP, via their respective kinases, usually cause relaxation by either attenuating Ca 2ϩ signals or by more direct interactions with the contractile machinery (28 -31).…”

Adenylyl cyclase-dependent axonal targeting in the olfactory system

“…1B). A short, possibly similar, Ac3 variant has previously been reported in male germ and smooth muscle cells (Gautier-Courteille et al, 1998;Wong et al, 2001). …”

Rosiglitazone Inhibits Acyl-CoA Synthetase Activity and Fatty Acid Partitioning to Diacylglycerol and Triacylglycerol via a Peroxisome Proliferator–Activated Receptor-γ–Independent Mechanism in Human Arterial Smooth Muscle Cells and Macrophages

“…Isolation and culture of murine SMCs. Normal murine SMCs were isolated from the thoracic aorta of male C57BL/6 mice via enzymatic digestion (13). Isolation of murine peritoneal macrophages.…”