Enhanced expression of Giα proteins contributes to the hyperproliferation of vascular smooth muscle cells from spontaneously hypertensive rats via MAP kinase- and PI3 kinase-independent pathways

Vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR) exhibit hyperproliferation, enhanced MAP kinase (MAPK) activity, and overexpression of Giα proteins. This study was undertaken to examine whether the overexpression of Giα proteins contributes to the hyperproliferation of VSMC of SHR through MAPK signaling. The hyperproliferation of VSMC from SHR in the absence and presence of angiotensin II was restored towards those in Wistar-Kyoto (WKY) rats levels by pertussis toxin (PT) treatment. In addition, siRNA knockdown of Giα proteins also resulted in the attenuation of hyperproliferation towards control levels. The overexpression of Giα proteins was also inhibited by MAPK and PI3 kinase (PI3K) inhibitors. In addition, the hyperproliferation and enhanced phosphorylation of ERK1/2 and Akt in VSMC from SHR were attenuated towards WKY levels by the inhibitors of MAPK, PI3K, c-Src, and antioxidants, whereas PT was unable to attenuate the enhanced phosphorylation of ERK1/2 and Akt. Furthermore, 8Br-cAMP and forskolin also attenuated the hyperproliferation of VSMC from SHR. These results suggest that the hyperproliferation of VSMC from SHR may be attributed to the enhanced expression of Giα proteins and increased activation of MAPK and PI3 kinase. However, Giα-mediated hyperproliferation may not be mediated through MAPK- and PI3 kinase-dependent pathways and may involve decreased levels of intracellular cAMP. Key words: VSMC proliferation, MAP kinase/PI3 kinase, Gi proteins, oxidative stress, SHR. Chez les SHR (pour spontaneously hypertensive rat), on observe une hyperproliferation des cellules musculaires lisses vasculaires (CMLV) ainsi qu'une augmentation de l'activite de la MAP kinase (MAPK) et une surexpression des proteins Giα. Dans la presente etude, nous avons tente de determiner si la surexpression des proteins Giα contribue a l'hyperproliferation des CMLV chez le rat SHR par l'intermediaire de la voie de signalisation de la MAPK. En utilisant la toxine pertussique (TP) en presence et en absence d'angiotensine II, nous avons retabli l'hyperproliferation des CMLV observee chez les rats SHR vers les niveaux observes chez les rats Wistar-Kyoto (WKY). De plus, le silencage des proteins Giα par siRNA a aussi permis d'attenuer l'hyperproliferation vers des niveaux que l'on retrouvait chez les temoins. La surexpression des proteins Giα a aussi ete entravee par les inhibiteurs de la MAPK et du PI3 kinase (PI3K). En outre, les inhibiteurs de la MAPK, du PI3K, et de c-Src ainsi que les antioxydants permettaient d'attenuer l'hyperproliferation et l'accroissement de la phosphorylation d'ERK1/2 et d'Akt dans les CMLV des rats SHR, alors que la TP ne permettait pas d'attenuer l'accroissement de la phosphorylation d'ERK1/2 et d'Akt. Par ailleurs, le 8Br-cAMP et la forskoline ont aussi permis d'attenuer l'hyperproliferation des CMLV chez le rat SHR. Ces resultats laissent entendre que l'hyperproliferation des CMLV chez le rat SHR pourrait etre attribuable a l'expression accrue des proteins Giα et d'une augmentation de l'activation de la MAPK ou de la PI3K. Toutefois, les mecanismes a l'origine de l'hyperproliferation reliee aux proteins Giα pourraient ne pas emprunter les voies de signalisation dependant de la MAPK et de la PI3K, mais plutot passer par la diminution des concentrations intracellulaires d'AMPc. [Traduit par la Redaction] Mots-cles: proliferation des CMLV, MAP kinase/PI3 kinase, proteines Gi, stress oxydatif, rat SHR.
Introduction Guanine nucleotide-binding regulatory proteins (G proteins), a family of GTP-binding proteins, play an important role in the regulation of a variety of physiological functions, including blood pressure, through the [...]