title: Hyperglycemia induced cell growth and gene expression via the serum response element through RhoA and Rho-kinase in vascular smooth muscle cells.
abstract: The impressive correlation between cardiovascular disease and alterations in glucose metabolism has raised the likelihood that atherosclerosis, heart failure, and type 2 diabetes may share common antecedents. Postprandial hyperglycemia has been shown to play an important role on the onset and development of heart failure and cerebral infarction in several large-scale clinical trials. Recently, chronic hyperglycemia has been reported to enhance the vasoconstrictor response by Rho-kinase. We have previously reported that phenylephrine enhanced the vasoconstrictor response in a spontaneous diabetes mellitus OLETF (Otsuka-Long-Evane-Tokushima fatty) rat model. However, the mechanism of hyperglycemia in these reactions, particularly the influence of hyperglycemia on the signal transduction pathway, is still not well understood. We, therefore, examined the effect of hyperglycemia on the cell growth and gene expression of rat aortic smooth-muscle cells (RASMCs). Hyperglycemia accelerated the growth of RASMCs in a concentration-dependent manner. Furthermore, the c-fos gene expression was also increased by hyperglycemia. Phenylephrine activated the c-fos gene expression. Hyperglycemia augmented the phenylephrine-induced c-fos gene expression synergistically in a dose dependent manner. The deletion analysis revealed that the c-fos serum response element (SRE) accounts for the c-fos gene expression. RhoA, and Rho-kinase were involved in hyperglycemia-induced c-fos gene expression. An HMG-CoA reductase inhibitor, Pitavastatin, inhibited these hyperglycemia-augmented reactions by inhibiting RhoA. Hyperglycemia itself increased the cell growth and gene expression. Furthermore, it modifies and augments the cell growth and gene expression by alpha1-AR-mediated stimulation. Statin might therefore be effective for the treatment of hyperglycemia-induced cardiovascular dysfunction.
authors.affiliation: Department of Internal Medicine, Division of Coronary Heart Disease, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Kai
authors.initials: K
authors.lastname: Ishiko
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Sakoda
authors.forename: Takahumi
authors.initials: T
authors.lastname: Akagami
authors.forename: Toshio
authors.initials: T
authors.lastname: Naka
authors.forename: Takashi
authors.initials: T
authors.lastname: Doi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tsujino
authors.forename: Tohru
authors.initials: T
authors.lastname: Masuyama
authors.forename: Mitsumasa
authors.initials: M
authors.lastname: Ohyanagi
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D015971:Gene Expression Regulation, Enzymologic; D006943:Hyperglycemia; D009131:Muscle, Smooth, Vascular / Q000201:enzymology*; D032389:Myocytes, Smooth Muscle / Q000201:enzymology*; D051381:Rats; D027602:Serum Response Element; D015398:Signal Transduction; D054460:rho-Associated Kinases / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein