TY - JOUR T1 - The Soluble Guanylate Cyclase Stimulator BAY 41-2272 Inhibits Vascular Smooth Muscle Growth through the cAMP-Dependent Protein Kinase and cGMP-Dependent Protein Kinase Pathways JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 394 LP - 402 DO - 10.1124/jpet.111.183400 VL - 339 IS - 2 AU - Chintamani N. Joshi AU - Danielle N. Martin AU - Jonathan C. Fox AU - Natalia N. Mendelev AU - Trisha A. Brown AU - David A. Tulis Y1 - 2011/11/01 UR - http://jpet.aspetjournals.org/content/339/2/394.abstract N2 - Vascular smooth muscle (VSM) proliferation and migration are key components in vessel remodeling. Cyclic nucleotide signaling is protective and has long-served as a therapeutic target against undesired VSM growth. The present work analyzed the effects of the soluble guanylate cyclase (sGC) stimulator 3-(4-amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine [BAY 41-2272 (BAY)] on VSM growth, and we hypothesize that BAY has the capacity to reduce proliferation and migration via cyclic nucleotide-driven kinase signaling. Perivascular BAY postballoon injury reduced neointimal growth by ∼40% compared with vehicle controls after 2 weeks. In VSM cells, BAY (10 μM) reduced proliferation by ∼40% after 72 h and migration by ∼40% after 6 h and ∼60% after 18 h without deleterious effects on cell viability. cGMP content peaked (248×) 20 min after BAY treatment and remained elevated (140×) through 60 min; however, BAY did not affect cAMP levels compared with controls. Conventional and In-Cell Western analyses showed increases in vasodilator-stimulated phosphoprotein (VASP) phosphorylation (pVASP) at serines 239 (3×) and 157 (2×), respective markers of cGMP- and cAMP-directed protein kinases (PKG and PKA, respectively). The PKG inhibitor YGRKKRRQRRRPPLRKKKKKH peptide (DT-2) completely reversed BAY-mediated increases in pVASPSer239 and BAY-mediated inhibition of migration. In comparison, the PKA inhibitor peptide PKI further potentiated BAY-stimulated pVASPSer157 and pVASPSer239 and partially reversed the antiproliferative effects of BAY. This is the first report demonstrating the effectiveness of BAY in reducing neointimal growth with direct evidence for PKG-specific antimigratory and PKA-specific antiproliferative mechanisms. Conclusively, the sGC stimulator BAY reduces VSM growth through cGMP-dependent PKG and PKA processes, providing support for continued evaluation of its clinical utility. ER -