活性维生素D在老年高血压血管平滑肌氧化应激中的作用及机制研究

Preventing and controlling elderly hypertension is one of the primary issues medical community faces with. The overall level of Vitamin D is relatively low in Chinese elderly population. Through applying 1α(OH)ase gene knock-out (1α(OH)ase-/-) mouse model, we demonstrated that deficiency of endogenous 1,25(OH)2D3, the active form of Vitamin D, would trigger oxidative stress and increase RAS activation in vascular smooth muscle cell (VSMC), leading to an blood pressure elevation. We also discovered serum 1,25(OH)D in elderly hypertensive patients was negatively correlated with their blood pressure and serum indicators of oxidative stress were higher in Vitamin D deficiency patients than those in normal controls. Therefore, based on these results, we hypothesize that 1,25(OH)2D3 deficiency may induce hypertension by enhancing oxidative stress in VSMC and RAS activity through PLC/PKC/MAPK pathway. To test this hypothesis, we intend to investigate the molecular mechanism of 1,25(OH)2D3 deficiency induced oxidative stress and up-regulated RAS activity through experiments with old 1α(OH)ase-/- mice and elderly hypertensive patients. By feeding subjects with exogenous 1,25(OH)2D3 rescue diet, we intend to explore the mechanism through which Vitamin D plays a role in blood pressure reduction and blood vessel protection. Our study will provide basic and clinical evidences for the application of 1,25(OH)2D3 in the prevention and control of elderly hypertension.

老年高血压的防治问题是医学界研究的热点。我国老年人维生素D水平整体偏低。本课题组在1α羟化酶基因敲除小鼠模型中证实内源性活性维生素D (1,25(OH)2D3)缺乏引起血管平滑肌细胞内氧化应激及RAS活性增加，导致小鼠血压升高。通过对老年高血压病例的研究，我们发现血清 1,25(OH)D浓度与血压呈负相关，且维生素D缺乏组的血清氧化应激指标高于维生素D正常组。我们根据前期研究成果提出：1,25(OH)2D3缺乏通过PLC/PKC/MAPK通路增加血管平滑肌细胞氧化应激及RAS活性，引起高血压。为证实这一假说，拟采用老龄1α羟化酶基因敲除小鼠模型及老年高血压病例为研究对象，探索1,25(OH)2D3缺乏引起的氧化应激及RAS活性增加的分子机制；通过补充外源性1,25(OH)2D3，探索其降压及保护血管的作用机制。本研究将为1,25(OH)2D3在老年高血压防治中的应用提供理论基础及临床指导。

老年高血压的防治问题是医学界研究的热点。我国老年人维生素D水平整体偏低。本课题组在1α羟化酶基因敲除小鼠模型中证实内源性活性维生素D (1,25(OH)2D3)缺乏引起血管平滑肌细胞内氧化应激及RAS活性增加，导致小鼠血压升高。通过对老年高血压病例的研究，我们发现血清 1,25(OH)D浓度与血压呈负相关，且维生素D缺乏组的血清氧化应激指标高于维生素D正常组。我们根据前期研究成果提出：1,25(OH)2D3缺乏增加血管平滑肌细胞氧化应激及RAS活性，引起高血压。为证实这一假说，拟采用老龄维生素D受体基因敲除（VDR-/-）小鼠模型及老年高血压病例为研究对象，探索1,25(OH)2D3缺乏引起的氧化应激及RAS活性增加的分子机制。本研究将为1,25(OH)2D3在老年高血压防治中的应用提供理论基础及临床指导。