title: Serum and glucocorticoid-regulated kinase 1 promotes vascular smooth muscle cell proliferation via regulation of β-catenin dynamics.
abstract: In response to arterial intimal injury vascular smooth muscle cells (VSMCs) within the vessel wall proliferate upon exposure to growth factors, accumulate, and form a neointima that can occlude the vessel lumen. Serum and glucocorticoid inducible kinase 1 (SGK1) is a growth factor-responsive kinase; however its role in VSMC proliferation is not fully understood. Here, we examined growth factor-dependent regulation of SGK1 and defined a molecular role for SGK1 in stimulation of VSMC proliferation. We found that stimulation of VSMCs with the pro-proliferative growth factor, platelet-derived growth factor BB (PDGF) significantly increased SGK1 mRNA, protein, and kinase activity in aortic VSMCs in vitro. To test the hypothesis that activation of SGK1 activity promotes VSMC proliferation, we examined the effects of stable expression of constitutively active (S422D) and kinase-defective (S422A) mutants of SGK1 on VSMC growth. We found that activation of SGK1 increased, whereas interference of SGK1 signaling inhibited VSMC growth in vitro. Consistent with these findings, expression of the S422D mutant augmented both basal and PDGF-induced BrdU uptake in VSMCs. Conversely, PDGF-induced BrdU uptake was attenuated in VSMCs expressing S422A. Furthermore, we determined that activated SGK1 enhanced basal and PDGF-dependent G1→S cell cycle transition, whereas dominant-negative SGK1 abrogated G1→S cell cycle transition under similar conditions. Downstream signaling by active SGK1 induced basal and PDGF-induced phosphorylation of glycogen synthase kinase 3β, an effect which was attenuated when SGK1 activity was blocked by expression of the kinase-defective mutant, S422A. We also found that transfection of S422D enhanced β-catenin-nuclear localization and activation of the TOP/Flash and cyclin D1 transcriptional reporters. These effects were significantly blunted in VSMCs transfected with the S422A mutant. Our results provide compelling evidence of a role for SGK1 in stimulation of arterial VSMC growth via regulation of β-catenin dynamics and implicate SGK1 in the progression of intimal narrowing following arterial injury. Hence, the findings presented here point to inhibition of SGK1 activity as a novel therapeutic approach for the treatment of occlusive vascular diseases.
authors.affiliation: Cardiovascular Research Institute, Morehouse School of Medicine, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhong
authors.affiliation: Cardiovascular Research Institute, Morehouse School of Medicine, United States.
authors.forename: Babayewa
authors.initials: B
authors.lastname: Oguljahan
authors.affiliation: Cardiovascular Research Institute, Morehouse School of Medicine, United States.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Duke University School of Medicine, United States.
authors.forename: James
authors.initials: J
authors.lastname: Nelson
authors.affiliation: Cardiovascular Research Institute, Morehouse School of Medicine, United States.
authors.forename: Liliana
authors.initials: L
authors.lastname: Hernandez
authors.affiliation: Department of Physiology, Morehouse School of Medicine, United States; Cardiovascular Research Institute, Morehouse School of Medicine, United States.
authors.forename: Minerva
authors.initials: M
authors.lastname: Garcia-Barrio
authors.affiliation: Department of Physiology, Morehouse School of Medicine, United States; Cardiovascular Research Institute, Morehouse School of Medicine, United States. Electronic address: sfrancis@msm.edu.
authors.forename: Sharon C
authors.initials: SC
authors.lastname: Francis
mesh_terms: D000818:Animals; D000077214:Becaplermin; D002460:Cell Line; D049109:Cell Proliferation / Q000235:genetics*; D019938:Cyclin D1 / Q000378:metabolism; D016193:G1 Phase / Q000235:genetics; D017874:Immediate-Early Proteins / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D010766:Phosphorylation / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism; D051381:Rats; D016196:S Phase / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D051176:beta Catenin / Q000378:metabolism*; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D000077214:Becaplermin; D019938:Cyclin D1; D017874:Immediate-Early Proteins; D017346:Protein Serine-Threonine Kinases; D020574:Proto-Oncogene Proteins c-sis; D051176:beta Catenin; D000099184:Serum-Glucocorticoid Regulated Kinases
keywords: Aortic smooth muscle cell; Beta-catenin; Cell cycle; Proliferation; SGK1