RAS激活和MMP-9/TIMP-1失衡在寒潮诱发脑卒中过程中的作用及机制研究

Epidemiological studies and clinical observations have indicated that cold temperature triggers stroke events in those at risk. However, the underlying mechanisms are still unknown. Matrix metalloproteinase-9 (MMP-9) has been found to be associated with the formation, progression and rupture of atherosclerotic plaques and cerebral aneurysms, which is the pathological basis of stroke, respectively. Tissue inhibitor of metalloproteinases-1(TIMP-1) is the endogenous tissue inhibitor of MMP-9. There is a balance between MMP-9 and TIMP-1 in physiological conditions. Cold temperature activates the circulating and tissue RAS。Ang II has been implicated in the inducing MMP-9 expression and activation. An imbalance between MMP-9 and TIMP-1 could cause large increases in MMP-9 and may facilitate destabilization and rupture of atherosclerotic plaques or cerebral aneurysms, resulting in acute stroke events. To examine this hypothesis, we evaluate the effects of cold wave, angiotensin-converting enzyme inhibitor captopril and recombinant TIMP-1 on AngII, MMP-9 and TIMP-1 in hypertensive rats, respectively, and furthermore to analyze the associations of these factors with structural changes of vessels, and with cold wave-induced stroke. This study may bring a new breakout for pathogenic mechanism of cold wave-induced stroke and might serve novel strategies for the prevention of cold wave-induced stroke.

流行病学调查及临床观察均发现低温可诱发脑卒中。然而，其潜在的机制仍不明确。研究显示MMP-9与动脉粥样硬化和脑动脉瘤的形成、发展和破裂有关，这是脑卒中发病的主要病理基础。TIMP-1是MMP-9的内源性抑制剂，生理条件下两者之间保持平衡。寒冷可激活循环和组织的肾素-血管紧张素系统，而血管紧张素II可诱导MMP-9表达和激活，MMP-9/TIMP-1失衡可能导致动脉粥样硬化斑块或脑动脉瘤破裂触发脑卒中。本研究分别观察寒潮、血管紧张素转化酶抑制剂卡托普利和重组TIMP-1对高血压模型血液和脑血管中AngII、MMP-9和TIMP-1的影响，以及它们变化与脑血管结构改变和寒潮诱发脑卒中的关系。研究有望为寒潮诱发脑卒中发病机制研究带来突破，为预防性干预提供靶点。

背景：众多观察性流行病学和临床观察表明寒冷暴露增加危险人群的卒中发生率。然而，寒冷诱脑发卒中的内在机制尚未阐明。本研究探究肾素-血管紧张素系统激活和基质金属蛋白酶-9（MMP-9）/组织型基质金属蛋白酶抑制剂-1(TIMP-1)失衡在寒潮诱发高血压大鼠脑卒中过程中的作用，评估血管紧张素转化酶抑制剂卡托普利和重组人组织型基质金属蛋白酶抑制剂-1(rhTIMP-1)在此过程中的作用。方法：首先，SD大鼠随机分成四组：假手术组，2K-2C组，2K-2C+captopril组，2K-2C+rhtimp-1组；然后每组又被随机分为寒潮组（ACE）和非寒潮组（NACE）两个亚组。双肾-双夹法制作肾血管性高血压大鼠（RHR）模型，血压稳定后，将各组大鼠分别置于改良RXZ-328A型人工智能气候箱中进行寒潮（相对湿度65% ，温度22°C，照明12 h，4°C，黑暗12 h为1个循环）和非寒潮（相对湿度65% ，温度22°C，照明12 h，22°C，黑暗12 h为1个循环）处理，共3个循环。气候箱处理后统计卒中发病率，检测血浆和脑皮层的血管紧张素II（AngII）、MMP-9、TIMP-1水平和脑皮层的基质金属蛋白酶（MMPs）活性。结果：慢性高血压明显上调血浆和脑皮层AngII与MMP-9表达；而TIMP-1未有相应的上调；RHR大鼠脑组织和主动脉血管MMP-9的表达均明显高于假手术组 (均P< 0. 05)，收缩压与血液、脑及血管组织中的MMP- 9水平均呈正相关(r=0.557，r=0.774和r=0.661，均P< 0. 05)，寒潮可进一步上调血浆和脑皮层的AngII与MMP-9水平，而TIMP-1水平则无明显增加。血管紧张素转化酶抑制剂卡托普利和rhTIMP-1不仅抑制寒潮后AngII和MMP-9增加和MMPs的活性，并且可降低脑卒中发病率。研究还发现血浆MMP-9水平与寒潮诱发脑卒中独立相关(OR, 1.17; 95% CI, 1.08 to 1.32; P<0.007)；而收缩压, TIMP-1或 MMP-9/TIMP-1比值与寒潮诱发脑卒中无相关性。结论：寒冷可通过激活RAS上调MMP-9加剧MMP-9/TIMP-1失衡诱发脑卒中，而卡托普利和rhTIMP-1通过抑制寒潮后MMP-9上调，减弱MMP-9/TIMP-1失衡对寒冷诱发脑卒中起到保护作用。