Magnesium Lithospermate B rescues endothelial dysfunction in diabetes mellitus and acts primarily via the PI3-K/Akt and hexosamine pathway

초록

Salvia miltiorrhizae radix is a popular Chinese herbal medicine for the treatment of cardiovascular diseases. This study was designed to investigate the effects of magnesium lithospermate B (LAB), the active compound of Salvia miltiorrhizae, on endothelial dysfunction associated with diabetes mellitus using cultured endothelial cells and an animal model of type 2 diabetes. The effect of LAB on vasodilatory function in Otsuka Long-Evans Tokushima Fatty (OLETF) type 2 diabetic rats was assessed. The ability of LAB to prevent hyperglycemia induced inhibition of endothelial nitric oxide synthase (eNOS) activity and apoptosis in cultured human aortic endothelial cells (HAECs) and the underlying mechanism associated with this effect was evaluated. LAB rescued the inhibition of eNOS activity and eNOS phosphorylation in endothelial cells cultured in hyperglycemia. LAB induced eNOS phosphorylation was dependent on Akt phosphorylation and was associated with a decreased O-glc NAC protein modification of eNOS. LAB also increased nuclear factor E2-related factor-2 (Nrf2) activation through a PI3 kinse/ Akt pathway dependent manner. However, increased eNOS phosphorylation by LAB was not changed by inhibiting nrf2 activation suggesting an nrf2-independent pathway. LAB was able to decrease oxidative stress caused by high glucose and was able to decrease hyperglycemia induced endothelial cell apoptosis. In OLETF rats endothelium-dependent vasodilation was impaired compared with lean control LETO rats. LAB treatment for 20weeks starting at 12weeks, was able to attenuate the decrease in endothelium-dependent vasodilation in OLETF rats. LAB is a naturally occurring antioxidant and activator of endothelial nitric oxide synthase that ameliorates endothelial dysfunction in diabetes by enhancing vasodilation. LAB may be a promising drug for the prevention and treatment of endothelial dysfunction associated with diabetes mellitus.