title: Antigrowth properties of BAY 41-2272 in vascular smooth muscle cells.
abstract: 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, on 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 protein kinases, and differential vasodilator-stimulated phosphoprotein phosphorylation. BAY significantly elevated cyclin E expression, decreased expression of the regulatory cyclin-dependent kinases -2 and -6, increased expression of cell cycle inhibitory p21 WAF1/Cip1 and p27 Kip1, 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.
authors.affiliation: Cardiovascular Disease Research Program, J.L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, Durham, NC, USA.
authors.forename: Natalia N
authors.initials: NN
authors.lastname: Mendelev
authors.forename: Verietta S
authors.initials: VS
authors.lastname: Williams
authors.forename: David A
authors.initials: DA
authors.lastname: Tulis
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000502:physiology; D006152:Cyclic GMP / Q000502:physiology; D019927:Cyclin E / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000096:biosynthesis; D051361:Cyclin-Dependent Kinase 6 / Q000096:biosynthesis; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000096:biosynthesis; D006131:Growth Inhibitors / Q000494:pharmacology*; D006162:Guanylate Cyclase; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists; D015398:Signal Transduction / Q000187:drug effects; D000071756:Soluble Guanylyl Cyclase
chemical_list: C423582:3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine; D019927:Cyclin E; D050759:Cyclin-Dependent Kinase Inhibitor p21; D006131:Growth Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D018160:Receptors, Cytoplasmic and Nuclear; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000242:Cyclic AMP; D051416:Focal Adhesion Protein-Tyrosine Kinases; D051357:Cyclin-Dependent Kinase 2; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP