Journal
JOURNAL OF CARDIOVASCULAR PHARMACOLOGY
Volume 53, Issue 2, Pages 121-131Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/FJC.0b013e31819715c4
Keywords
BAY 41-2272; cyclic GMP; cyclins; protein kinases; vascular smooth muscle
Funding
- NHLBI NIH HHS [HL59868, R25 HL059868, R01 HL081720, HL81720, UH1 HL059868, R01 HL081720-03] Funding Source: Medline
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Vascular smooth muscle (VSM) growth is integral in the pathophysiology of blood vessel diseases, and identifying approaches that have capacity, to regulate VSM growth is critically essential. Cyclic nucleotide signaling has been generally considered protective in cardiac and vascular tissues and has been the target of numerous basic science and clinical studies. In this project, the influence of BAY 41-2272 (BAY), a recently described soluble guanylate cyclase stimulator and inducer of cyclic guanosine monophosphate (cGMP) synthesis, oil VSM cell growth was analyzed. In rat A7R5 VSM cells, BAY significantly reduced proliferation in a dose- and time-dependent fashion. BAY activated cGMP and cyclic adenosine monophosphate (cAMP) signaling evidenced through elevated cGMP and cAMP content, increased expression of cyclic nucleotide-dependent proteir kinases, and differential vasodilator-stimulated phosphoprotein phosphorylation. BAY significantly elevated cyclin F expression, decreased expression of the regulatory cyclin-dependent kinases -2 and -6, increased expression of cell cycle inhibitory p21(WAFI/Cipl) and p27(Kipl), and reduced expression of phosphorylated focal adhesion kinase, These comprehensive findings provide first evidence for the antigrowth cell cycle- regulatory properties of the neoteric agent, BAY 41-2272, in VSM and lend Support for its continued study in the clinical and basic cardiovascular sciences.
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