RESUMO
Diabetes mellitus is a major independent risk factor for the development of cardiovascular disease, and both type 1 and type 2 diabetes have been shown to accelerate the development of atherosclerosis, the underlying cause of most myocardial infarctions. Despite the profound clinical importance of vascular disease in patients with diabetes mellitus, our understanding of the relative contributions of insulin resistance and hyperglycemia to atherogenesis is not complete. Furthermore, the molecular and cellular pathways that are involved in disease progression are not clear. In this review, we summarize our current understanding of the potential mechanisms that link diabetes to atherosclerosis and indicate existing gaps in our knowledge.
Assuntos
Aterosclerose/fisiopatologia , Diabetes Mellitus Tipo 1/fisiopatologia , Diabetes Mellitus Tipo 2/fisiopatologia , Angiopatias Diabéticas/fisiopatologia , Hiperglicemia/fisiopatologia , Aterosclerose/sangue , Aterosclerose/prevenção & controle , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/genética , Angiopatias Diabéticas/sangue , Angiopatias Diabéticas/genética , Progressão da Doença , Retículo Endoplasmático/metabolismo , Feminino , Humanos , Hiperglicemia/sangue , Hiperglicemia/genética , Resistência à Insulina/genética , Masculino , Estresse Oxidativo , Fatores de Risco , Transdução de SinaisRESUMO
In this study, we begin to investigate the underlying mechanism of leptin-induced vascular calcification. We found that treatment of cultured bovine aortic smooth muscle cells (BASMCs) with leptin (0.5-4 µg/ml) induced osteoblast differentiation in a dose-dependent manner. Furthermore, we found that leptin significantly increased the mRNA expression of osteopontin and bone sialoprotein, while down-regulating matrix gla protein (MGP) expression in BASMCs. Key factors implicated in osteoblast differentiation, including members of the Wnt signaling pathway, were examined. Exposure to leptin enhanced phosphorylation of GSK-3ß on serine-9 thereby inhibiting activity and promoting the nuclear accumulation of ß-catenin. Transfection of BASMCs with an adenovirus that expressed constitutively active GSK-3ß (Ad-GSK-3ß S9A) resulted in a >2-fold increase in GSK-3ß activity and a significant decrease in leptin-induced alkaline phosphatase (ALP) activity. In addition, qRT-PCR analysis showed that GSK-3ß activation resulted in a significant decrease in the expression of osteopontin and bone sialoprotein, but a marked increase in MGP mRNA expression. When taken together, our results suggest a mechanism by which leptin promotes osteoblast differentiation and vascular calcification in vivo.
