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1 Department of Pharmacology, University of Alabama at Birmingham, Birmingham, AL, USA
2 Department of Physiology, University of South Alabama, Mobile, AL, USA
* To whom correspondence should be addressed. E-mail: tlincoln{at}usouthal.edu.
NO and cGMP have anti-growth and anti-inflammatory effects on the vessel wall in response to injury. It is well established that following vascular injury, pro-inflammatory cytokines are involved in vascular wall remodeling. The purpose of this study was to ascertain the signaling mechanisms involved in cGMP-dependent protein kinase (PKG) suppression by inflammatory cytokines in primary bovine aortic vascular smooth muscle cells (VSMC). Interleukin-I
(IL-I), tumor necrosis factor-
(TNF-), and LPS decreased the mRNA and protein levels of PKG in VSMC. IL-I, TNF- and LPS increased iNOS expression and cGMP production. Treatment of cells with selective inhibitors of iNOS or soluble guanylate cyclase (sGC) reversed the down-regulation of PKG expression induced by cytokines and LPS. The NO donor, DETA NONOate, and YC-1, a NO-independent sGC activator, decreased PKG mRNA and protein expression in bovine aortic VSMC. Cyclic nucleotide analogues (8p-CPT cGMP and 8p-CPT cAMP) also suppressed PKG mRNA and protein expression. However, 8p-CPT cAMP was more effective than 8p-CPT cGMP in decreasing PKG mRNA levels. Selective inhibition of PKA using Rp-8p-CPT cAMPS prevented the down-regulation of PKG by LPS. In contrast, the inhibitor of PKG, Rp-8p-CPT cGMPS, had no effect on LPS-induced inhibition of PKG mRNA and protein expression. These studies suggest that cross-activation of PKA in response to iNOS expression by inflammatory mediators down-regulate PKG expression in bovine aortic VSMC.
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