Pressure overload-induced transient oxidative stress mediates perivascular inflammation and cardiac fibrosis through angiotensin II
Pressure overload-induced transient oxidative stress mediates perivascular inflammation and cardiac fibrosis through angiotensin II
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DOI：
10.1291/hypres.29.711
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发表时间：
2006-09-01
影响因子：
5.4
通讯作者：
Imaizumi, Tsutomu
中科院分区：
文献类型：
--
作者：
Kai, Hisashi;Mori, Takahiro;Imaizumi, Tsutomu
氧化应激与多种心血管疾病的发病机制有关。我们已经表明，在Wistar大鼠肾上腺主动脉缩窄（AC），压力超负荷诱导的短暂的血管周围炎症（单核细胞趋化蛋白-1（MCP-1）诱导和巨噬细胞的积累）在早期阶段是反应性心肌纤维化和舒张功能障碍的决定因素在晚期阶段。因此，我们研究了活性氧在AC大鼠心脏重构中的作用。分别用二氢乙锭染色和4-羟基-2-壬烯醛（4-HNE）染色评估超氧化物的产生和脂质过氧化的足迹。在假手术组，心脏内几乎未发现二氢乙锭和4-HNE信号。在第3天，AC大鼠主要在心肌内动脉壁显示二氢乙锭信号，而在心肌中弥漫性观察到适度的4-HNE染色。尽管持续高血压，这些信号在第14天下降到较低水平。慢性给药亚降压剂量的血管紧张素II 1型受体阻滞剂坎地沙坦减少压力超负荷诱导的二氢乙锭和4-HNE信号在第3天。此外，坎地沙坦在第3天降低MCP-1诱导和巨噬细胞浸润，在第14天防止心肌纤维化，而不影响左心室和心肌细胞肥大。总之，急性压力超负荷引起的自限性超氧化物的产生主要在血管壁。活性氧的产生可能是导致血管周围炎症和随后的心肌纤维化的原因之一。血管紧张素II被认为对活性氧的产生具有非压力依赖性作用。
Oxidative stress is implicated in the pathogenesis of various cardiovascular diseases. We have shown that in Wistar rats with a suprarenal aortic constriction (AC), pressure overload-induced transient perivascular inflammation (monocyte chemoattractant protein-1 [MCP-1] induction and macrophage accumulation) in the early phase is the determinant of reactive myocardial fibrosis and resultant diastolic dysfunction in the late phase. Thus, we investigated the role of reactive oxygen species production in cardiac remodeling in AC rats. Superoxide production and the footprint of lipid peroxidation were assessed using dihydroethidium staining and immunohistostaining against 4-hydroxy-2-nonenal (4-HNE), respectively. In sham rats, dihydroethidium and 4-HNE signals were scarcely found in the heart. At day 3, AC rats showed dihydroethidium signals mainly in the intramyocardial arterial wall, whereas modest 4-HNE staining was observed diffusely in the myocardium. These signals declined to lower levels by day 14 despite sustained hypertension. Chronic administration of a subdepressor dose of an angiotensin II type 1 receptor blocker candesartan reduced the pressure overload-induced dihydroethidium and 4-HNE signals at day 3. Moreover, candesartan decreased MCP-1 induction and macrophage infiltration at day 3 and prevented myocardial fibrosis at day 14, without affecting left ventricle and myocyte hypertrophy. In conclusion, acute pressure overload induced self-limited superoxide production mainly in the vascular wall. The reactive oxygen species production would contribute to the perivascular inflammation and subsequent myocardial fibrosis. Angiotensin II was suggested to have a pressure-independent effect on the reactive oxygen species production.