title: cAMP attenuates the enhanced expression of Gi proteins and hyperproliferation of vascular smooth muscle cells from SHR: role of ROS and ROS-mediated signaling.
abstract: We previously showed that angiotensin II (ANG II)-induced overexpression of inhibitory G proteins (Gi) was attenuated by dibutyryl-cAMP (db-cAMP) in A10 vascular smooth muscle cells (VSMC). Since enhanced levels of endogenous ANG II contributed to the overexpression of Gi protein and hyperproliferation of VSMC from spontaneously hypertensive rats (SHR), the present study was therefore undertaken to examine if cAMP could also attenuate the overexpression of Gi proteins and hyperproliferation of VSMC from SHR and to explore the underlying molecular mechanisms responsible for this response. The enhanced expression of Giα proteins in VSMC from SHR and Nω-nitro-L-arginine methyl ester hypertensive rats was decreased by db-cAMP. In addition, enhanced inhibition of adenylyl cyclase by inhibitory hormones and forskolin-stimulated adenylyl cyclase activity by low concentration of GTPγS in VSMC from SHR was also restored to Wistar-Kyoto (WKY) levels by db-cAMP. Furthermore, db-cAMP also attenuated the hyperproliferation and the increased production of superoxide anion, NAD(P)H oxidase activity, overexpression of Nox1/Nox2/Nox4 and p47phox proteins, increased phosphorylation of PDGF-receptor (R), EGF-R, c-Src, and ERK1/2 to control levels. In addition, the protein kinase A (PKA) inhibitor reversed the effects of db-cAMP on the expression of Nox4 and Giα proteins and hyperproliferation of VSMC from SHR to WKY levels, while stimulation of the exchange protein directly activated by cAMP did not have any effect on these parameters. These results suggest that cAMP via PKA pathway attenuates the overexpression of Gi proteins and hyperproliferation of VSMC from SHR through the inhibition of ROS and ROS-mediated transactivation of EGF-R/PDGF-R and MAPK signaling pathways.
authors.affiliation: Department of Physiology, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Gusan
authors.forename: Madhu B
authors.initials: MB
authors.lastname: Anand-Srivastava
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics
chemical_list: D017382:Reactive Oxygen Species; D000242:Cyclic AMP; D019206:GTP-Binding Protein alpha Subunits, Gi-Go
keywords: Gi proteins; SHR; cAMP; cell proliferation; oxidative stress; vascular smooth muscle cells