Elevated Glucose Levels Promote Contractile and Cytoskeletal Gene Expression in Vascular Smooth Muscle via Rho/Protein Kinase C and Actin Polymerization

• Published in: The Journal of biological chemistry Vol. 291; no. 7; pp. 3552 - 3568
• Main Authors: Hien, Tran Thi, Turczyńska, Karolina M., Dahan, Diana, Ekman, Mari, Grossi, Mario, Sjögren, Johan, Nilsson, Johan, Braun, Thomas, Boettger, Thomas, Garcia-Vaz, Eliana, Stenkula, Karin, Swärd, Karl, Gomez, Maria F., Albinsson, Sebastian
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12-02-2016; American Society for Biochemistry and Molecular Biology
• Subjects: Actin Cytoskeleton - metabolism; Actin Cytoskeleton - pathology; actin polymerization; Aged; Animals; Atherosclerosis - enzymology; Atherosclerosis - metabolism; Atherosclerosis - pathology; Cardiac and Cardiovascular Systems; cell differentiation; Cells, Cultured; Clinical Medicine; Contractile Proteins - agonists; Contractile Proteins - genetics; Contractile Proteins - metabolism; Cytoskeletal Proteins - agonists; Cytoskeletal Proteins - genetics; Cytoskeletal Proteins - metabolism; diabetes; Diabetes Mellitus, Type 1 - complications; Diabetes Mellitus, Type 2 - complications; Diabetic Angiopathies - enzymology; Diabetic Angiopathies - metabolism; Diabetic Angiopathies - pathology; Gene Expression Regulation; glucose; Humans; Kardiologi; Klinisk medicin; Male; Medical and Health Sciences; Medicin och hälsovetenskap; Mice, Knockout; Mice, Mutant Strains; microRNA (miRNA); MicroRNAs - metabolism; Molecular Bases of Disease; Muscle, Smooth, Vascular - enzymology; Muscle, Smooth, Vascular - metabolism; Muscle, Smooth, Vascular - pathology; Protein Kinase C - chemistry; Protein Kinase C - metabolism; Rho (Rho GTPase); rho GTP-Binding Proteins - agonists; rho GTP-Binding Proteins - metabolism; rho-Associated Kinases - chemistry; rho-Associated Kinases - metabolism; Signal Transduction; vascular smooth muscle cells; actin polymerization; cell differentiation; glucose; microRNA (miRNA); Rho (Rho GTPase); diabetes; vascular smooth muscle cells
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1074/jbc.M115.654384

Both type 1 and type 2 diabetes are associated with increased risk of cardiovascular disease. This is in part attributed to the effects of hyperglycemia on vascular endothelial and smooth muscle cells, but the underlying mechanisms are not fully understood. In diabetic animal models, hyperglycemia results in hypercontractility of vascular smooth muscle possibly due to increased activation of Rho-kinase. The aim of the present study was to investigate the regulation of contractile smooth muscle markers by glucose and to determine the signaling pathways that are activated by hyperglycemia in smooth muscle cells. Microarray, quantitative PCR, and Western blot analyses revealed that both mRNA and protein expression of contractile smooth muscle markers were increased in isolated smooth muscle cells cultured under high compared with low glucose conditions. This effect was also observed in hyperglycemic Akita mice and in diabetic patients. Elevated glucose activated the protein kinase C and Rho/Rho-kinase signaling pathways and stimulated actin polymerization. Glucose-induced expression of contractile smooth muscle markers in cultured cells could be partially or completely repressed by inhibitors of advanced glycation end products, L-type calcium channels, protein kinase C, Rho-kinase, actin polymerization, and myocardin-related transcription factors. Furthermore, genetic ablation of the miR-143/145 cluster prevented the effects of glucose on smooth muscle marker expression. In conclusion, these data demonstrate a possible link between hyperglycemia and vascular disease states associated with smooth muscle contractility.