Abstract
BAY 41-2272 (BAY), a stimulator of soluble guanylyl cyclase, increases cyclic nucleotides and inhibits proliferation of vascular smooth muscle cells (VSMCs). In this study, we elucidated mechanisms of action of BAY in its regulation of vasodilator-stimulated phosphoprotein (VASP) with an emphasis on VSMC phosphodiesterases (PDEs). BAY alone increased phosphorylation of VASPSer239 and VASPSer157, respective indicators of PKG and PKA signaling. IBMX, a non-selective inhibitor of PDEs, had no effect on BAY-induced phosphorylation at VASPSer239 but inhibited phosphorylation at VASPSer157. Selective inhibitors of PDE3 or PDE4 attenuated BAY-mediated increases at VASPSer239 and VASPSer157, whereas PDE5 inhibition potentiated BAY-mediated increases only at VASPSer157. In comparison, 8Br-cGMP increased phosphorylation at VASPSer239 and VASPSer157 which were not affected by selective PDE inhibitors. In the presence of 8Br-cAMP, inhibition of either PDE4 or PDE5 decreased VASPSer239 phosphorylation and inhibition of PDE3 increased phosphorylation at VASPSer239, while inhibition of PDE3 or PDE4 increased and PDE5 inhibition had no effect on VASPSer157 phosphorylation. These findings demonstrate that BAY operates via cAMP and cGMP along with regulation by PDEs to phosphorylate VASP in VSMCs and that the mechanism of action of BAY in VSMCs is different from that of direct cyclic nucleotide analogs with respect to VASP phosphorylation and the involvement of PDEs. Given a role for VASP as a critical cytoskeletal protein, these findings provide evidence for BAY as a regulator of VSMC growth and a potential therapeutic agent against vasculoproliferative disorders.
Highlights
Vascular smooth muscle cell (VSMC) growth is an integral process in the pathophysiology of numerous cardiac and vascular disorders; approaches aimed at minimizing abnormal vascular smooth muscle cells (VSMCs) growth are of significant clinical and therapeutic interest
These findings demonstrate that BAY 41-2272 (BAY) operates via cyclic adenosine monophosphate (cAMP) and Cyclic guanosine monophosphate (cGMP) along with regulation by PDEs to phosphorylate vasodilator-stimulated phosphoprotein (VASP) in VSMCs and that the mechanism of action of BAY in VSMCs is different from that of direct cyclic nucleotide analogs with respect to VASP phosphorylation and the involvement of PDEs
THE EFFECT OF BAY-INDUCED INCREASES IN CYCLIC NUCLEOTIDES IN RAT PRIMARY VSMCs BAY 41-2272 increased the content of both cGMP and cAMP, with an increase observed for cGMP at 100 nM after 15 min (Figure 1A) and for cAMP at 1 nM after 5 min (Figure 1B)
Summary
Vascular smooth muscle cell (VSMC) growth is an integral process in the pathophysiology of numerous cardiac and vascular disorders; approaches aimed at minimizing abnormal VSMC growth are of significant clinical and therapeutic interest. Cyclic nucleotide signaling is considered antiproliferative in cardiac and vascular tissues and has been the target of numerous basic science and clinical studies (Feil et al, 2005; Tulis, 2008). Balloon angioplasty increases the expression and activity of PDE3 and PDE4 in VSMCs (Zhao et al, 2008) Both PDE3 and PDE4 contribute to the regulation of VSMC proliferation and cilostazol, a PDE3 inhibitor, has shown promise in clinical trials for treatment of restenosis (Douglas et al, 2005). PDE5 inhibitors such as Viagra and Revatio are currently in use for treatment of erectile dysfunction and pulmonary hypertension, respectively (Boolell et al, 1996; Hemnes and Champion, 2006), clearly showing clinical importance of PDEs
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