Calpain inhibition attenuates angiotensin II-induced abdominal aortic aneurysms and atherosclerosis in low-density lipoprotein receptor-deficient mice.
Calpain inhibition attenuates angiotensin II-induced abdominal aortic aneurysms and atherosclerosis in low-density lipoprotein receptor-deficient mice.
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DOI：
10.1097/fjc.0b013e318235d5ea
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发表时间：
2012-01
影响因子：
3
通讯作者：
Balakrishnan A
中科院分区：
文献类型：
--
作者：
Subramanian V;Uchida HA;Ijaz T;Moorleghen JJ;Howatt DA;Balakrishnan A
长期输注血管紧张素 II (AngII) 会加剧高胆固醇血症小鼠的动脉粥样硬化和腹主动脉瘤 (AAA) 形成。 AngII 诱导的 AAA 与内侧巨噬细胞积累和基质金属蛋白酶 (MMP) 激活相关。钙蛋白酶（一种钙激活的中性半胱氨酸蛋白酶）通过其内源性抑制剂钙蛋白酶抑制素的过度表达来抑制，可减轻小鼠体内 AngII 诱导的白细胞浸润、血管周围炎症和 MMP 激活。本研究的目的是确定钙蛋白酶的药理抑制是否会影响高胆固醇血症小鼠中 AngII 诱导的 AAA。雄性 LDL 受体 -/− 小鼠被喂食富含脂肪的饮食，并给予载体或钙蛋白酶特异性抑制剂 BDA-410（30 毫克/公斤/天），持续 5 周。喂养 1 周后，给小鼠注射 AngII (1,000 ng/kg/min) 4 周。 AngII 输注显着增加了主动脉钙蛋白酶蛋白和活性。 BDA-410 给药对血浆胆固醇浓度或 AngII 升高的收缩压没有影响。钙蛋白酶抑制显着减弱 AngII 诱导的 AAA 形成和动脉粥样硬化发展。 BDA-410 给药减弱了 MMP12、促炎细胞因子（IL-6、MCP-1）的激活和主动脉巨噬细胞的浸润。 BDA-410 给药显着减弱了巯基乙酸盐引起的腹腔巨噬细胞积聚。我们得出的结论是，使用 BDA-410 抑制钙蛋白酶可减弱 LDL 受体 -/− 小鼠中 AngII 诱导的 AAA 形成和动脉粥样硬化发展。
Chronic infusion of angiotensin II (AngII) augments atherosclerosis and abdominal aortic aneurysm (AAAs) formation in hypercholesterolemic mice. AngII-induced AAAs are associated with medial macrophage accumulation and matrix metalloproteinase (MMP) activation. Inhibition of calpain, a calcium-activated neutral cysteine protease, by overexpression of its endogenous inhibitor, calpastatin, attenuates AngII-induced leukocyte infiltration, perivascular inflammation, and MMP activation in mice. The purpose of this study was to define whether pharmacological inhibition of calpain influences AngII-induced AAAs in hypercholesterolemic mice. Male LDL receptor −/− mice were fed a fat-enriched diet and administered with either vehicle or a calpain-specific inhibitor, BDA-410 (30 mg/kg/day) for 5 weeks. After 1 week of feeding, mice were infused with AngII (1,000 ng/kg/min) for 4 weeks. AngII-infusion profoundly increased aortic calpain protein and activity. BDA-410 administration had no effect on plasma cholesterol concentrations or AngII-increased systolic blood pressure. Calpain inhibition significantly attenuated AngII-induced AAA formation and atherosclerosis development. BDA-410 administration attenuated activation of MMP12, pro-inflammatory cytokines (IL-6, MCP-1) and macrophage infiltration into the aorta. BDA-410 administration significantly attenuated thioglycollate-elicited macrophage accumulation in the peritoneal cavity. We conclude that calpain inhibition using BDA-410 attenuated AngII-induced AAA formation and atherosclerosis development in LDL receptor −/− mice.