Elevated Glucose Levels Promote Contractile and Cytoskeletal Gene Expression in Vascular Smooth Muscle via Rho/Protein Kinase C and Actin Polymerization |
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Authors: | Tran Thi Hien Karolina M. Turczyńska Diana Dahan Mari Ekman Mario Grossi Johan Sj?gren Johan Nilsson Thomas Braun Thomas Boettger Eliana Garcia-Vaz Karin Stenkula Karl Sw?rd Maria F. Gomez Sebastian Albinsson |
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Affiliation: | From the Departments of ‡Experimental Medical Sciences and ;§Clinical Sciences, Lund University, BMC D12, SE-221 84 Lund, Sweden and ;the ¶Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany, and ;the ‖Department of Clinical Sciences in Malmö, Lund University, 205 02 Malmö, Sweden |
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Abstract: | 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. |
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Keywords: | cell differentiation diabetes glucose microRNA (miRNA) Rho (Rho GTPase) vascular smooth muscle cells actin polymerization |
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