CD38调控高血压血管重塑的作用机制研究

Vascular remodeling is the important pathological change in hypertension, and is the pathological basis for the maintenance and aggravation of hypertension. The structure and function alternation of vascular smooth muscle cells (VSMCs) is the crucial process in vascular remodeling. CD38 is a multifunctional protein known to regulate immune response, Ca2+ and energy metabolism. However, the role of CD38 in pathological cardiovascular remodeling has remained unclear. In our previous study, we revealed that in angiotensin II-infused CD38 knockout mice, hypertension and vascular remodeling were efficiently alleviated. CD38 deficiency caused great decreases in blood pressure, media thickness, media:lumen ratio, and the deposition of collagen and elastin. The results indicated that CD38 deficiency might perform the protective effects against vascular remodeling via maintaining the structure and function of VSMCs. By using CD38-/- and other gene knockout mice, the proposal is (1) to investigate the potential protective effects of CD38 deficiency aganist the alternation of vascular reactivity, the enhancement of VSMCs hypertrophy, proliferation, migration and matrix production in pathogenesis of hypertension; (2) to identify the molecular mechanism of CD38-mediated cADPR-Ca2+ and/or NAD-SIRT1 signaling pathway and the downstream effector molecules in hypertension and vascular remodeling. The study will provide a potential preventative and therapeutic avenue for hypertension.

血管重塑是高血压病理改变的重要组成部分，是高血压维持、恶化的病理学基础。血管中膜层平滑肌细胞（VSMCs）结构和功能的改变是促进血管重塑的重要环节。CD38是调节免疫应答、Ca2+及能量代谢的多功能蛋白，但尚不清楚其调节心血管病理性重塑的作用及机制。我们前期工作发现CD38-/-小鼠显著缓解血管紧张素II诱导的高血压及血管重塑，即有效控制血压、抑制血管壁中膜层的增厚、降低中膜层:管腔内径比值，减少胶原和弹力蛋白沉积，提示CD38可能通过调控VSMCs的结构和功能缓解高血压及血管重塑。本研究拟使用CD38-/-等基因敲除小鼠，（1）探讨高血压疾病过程中，CD38基因敲除对血管反应性改变，VSMCs肥大、增殖、迁移和基质合成等病理变化的拮抗作用；（2）阐明CD38介导的cADPR-Ca2+和/或NAD-SIRT1信号通路及下游分子调控高血压及血管重塑的作用机制。以期为高血压的防治提供新的思路。

血管重塑是高血压病理改变的重要部分，是高血压维持、恶化的病理学基础。血管平滑肌细胞（VSMCs）的结构功能的改变是促进血管重塑的重要环节。CD38是一个多功能蛋白，分布广泛，在心血管系统的作用日益受到重视。但CD38如何调控心血管病理性重塑的作用机制，尚不明确。本课题发现CD38基因敲除小鼠能显著缓解血管紧张素II诱导的高血压及血管重塑，表现为有效控制血压，抑制血管壁中膜层的增厚，降低中膜层:管腔内径比值，减少胶原沉积，增加弹力蛋白；而采用骨髓嵌合小鼠的方法证实造血系统特性敲除CD38基因则不能有效缓解Ang II诱导的高血压和血管重塑，提示CD38通过调控VSMCs的结构功能缓解高血压及血管重塑。该结果拟用组织特异性基因敲除小鼠（平滑肌细胞CD38基因特异性敲除小鼠）进一步证实。此外，本课题研究证实：(1) CD38基因敲除通过激活NAD-SIRT1信号通路，抑制下游NOX1/NOX4介导的ROS的生成及氧化应激诱导的VSMCs衰老；并发现 (2) 衰老的VSMCs通过旁分泌作用调节非衰老VSMCs的增殖和肥大，CD38亦参与该旁分泌途径的调控。细胞间的“communication”及旁分泌作用的具体效应分子是该课题下一步探讨的重点内容。本课题从细胞NAD能量代谢和细胞间“communication”两方面，为高血压的防治提供新的思路和方法。

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