title: c-Src-dependent nongenomic signaling responses to aldosterone are increased in vascular myocytes from spontaneously hypertensive rats.
abstract: Aldosterone plays an important role in the pathogenesis of hypertension. We previously demonstrated that nongenomic signaling by aldosterone in vascular smooth muscle cells occurs through c-Src-dependent pathways. Here we tested the hypothesis that upregulation of c-Src by aldosterone plays a role in increased mitogen-activated protein (MAP) kinase activation, [3H]-proline incorporation, and NADPH-driven generation of reactive oxygen species, thereby inducing cell growth, collagen production, and inflammation, respectively, in vascular smooth muscle cells from spontaneously hypertensive rats. The time course of c-Src phosphorylation by aldosterone was shifted to the left in vascular myocytes from hypertensive animals. Aldosterone rapidly increased phosphorylation of p38 MAP kinase and extracellular signal-regulated kinase with significantly greater effects in cells from spontaneously hypertensive rats versus control cells (P<0.05). Aldosterone increased NADPH oxidase activity with significantly greater responses in vascular smooth muscle cells from hypertensive animals (P<0.05). These events were associated with enhanced [3H]proline incorporation (index of collagen synthesis) in cells from spontaneously hypertensive rats (P<0.05). The NADPH oxidase activity increase, collagen synthesis, c-Src, and MAP kinase phosphorylation induced by aldosterone were significantly reduced by eplerenone (selective mineralocorticoid receptor blocker) and PP2 (selective c-Src inhibitor). In conclusion, nongenomic signaling by exogenous aldosterone, mediated through c-Src, is increased in vascular smooth muscle cells from spontaneously hypertensive rats. Upregulation of c-Src signaling may be important in the profibrotic and proinflammatory actions of aldosterone in this genetic model of hypertension.
authors.affiliation: Ottawa Health Research Institute, University of Ottawa, Ottawa, Canada. gcallera@uottawa.ca
authors.forename: Glaucia E
authors.initials: GE
authors.lastname: Callera
authors.forename: Augusto C I
authors.initials: AC
authors.lastname: Montezano
authors.forename: Alvaro
authors.initials: A
authors.lastname: Yogi
authors.forename: Rita C
authors.initials: RC
authors.lastname: Tostes
authors.forename: Ying
authors.initials: Y
authors.lastname: He
authors.forename: Ernesto L
authors.initials: EL
authors.lastname: Schiffrin
authors.forename: Rhian M
authors.initials: RM
authors.lastname: Touyz
mesh_terms: D000450:Aldosterone / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006973:Hypertension / Q000378:metabolism*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D019255:NADPH Oxidases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011392:Proline / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism*; D051381:Rats; D011918:Rats, Inbred SHR / Q000378:metabolism*; D011921:Rats, Inbred WKY; D015398:Signal Transduction / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000450:Aldosterone; D011392:Proline; D019255:NADPH Oxidases; D016392:Proto-Oncogene Proteins pp60(c-src); D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases