Critical Role of Apoptosis Signal-Regulating Kinase 1 in Aldosterone/Salt-Induced Cardiac Inflammation and Fibrosis
Critical Role of Apoptosis Signal-Regulating Kinase 1 in Aldosterone/Salt-Induced Cardiac Inflammation and Fibrosis
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DOI：
10.1161/hypertensionaha.109.135392
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发表时间：
2009-09-01
期刊：
影响因子：
8.3
通讯作者：
Kim-Mitsuyama, Shokei
中科院分区：
文献类型：
--
作者：
Nakamura, Taishi;Kataoka, Keiichiro;Kim-Mitsuyama, Shokei
醛固酮/盐诱导的心血管损伤的分子机制仍有待确定。本研究旨在探讨凋亡信号调节激酶1（ASK 1）在醛固酮诱导的心肌损伤机制中的作用。我们比较了4周的醛固酮/盐治疗对野生型和ASK 1缺陷小鼠的体内作用。在野生型小鼠中，醛固酮输注加高盐摄入显著增加血压和尿白蛋白排泄，降低血浆钾浓度，并且这些醛固酮/盐的作用不受ASK 1缺乏的影响。因此，ASK 1似乎在醛固酮诱导的高血压和肾损伤中起次要作用。ASK 1缺乏也未能影响醛固酮诱导的心脏肥大。然而，ASK 1缺乏显著改善醛固酮诱导的心脏损伤，例如，心脏巨噬细胞浸润，单核细胞趋化蛋白1表达，间质纤维化，血管周围纤维化，转化生长因子β 1和I型胶原表达增加。因此，ASK 1参与醛固酮诱导的心脏炎症和纤维化。此外，增强NADPH氧化酶介导的心脏氧化应激引起的醛固酮输注显着减少ASK 1缺乏，这是与ASK 1缺乏显着改善醛固酮诱导的心脏Nox 2上调。此外，醛固酮/盐治疗显着增强心脏血管紧张素转换酶和血管紧张素II 1型受体在野生型小鼠的表达，而这些蛋白质的增强醛固酮/盐被废除的ASK 1缺陷。我们的研究结果表明，ASK 1是牵连在醛固酮/盐诱导的心脏炎症和纤维化，通过增强NADPH氧化酶介导的氧化应激和心脏的肾素-血管紧张素系统的上调。（高血压。2009; 54：544-551）。
The molecular mechanism underlying aldosterone/salt-induced cardiovascular injury remains to be defined. This work was undertaken to determine the role of apoptosis signal-regulating kinase 1 (ASK1) in the mechanism underlying aldosterone-induced cardiac injury in vivo. We compared the in vivo effects of 4 weeks of aldosterone/salt treatment on wild-type and ASK1-deficient mice. Aldosterone infusion plus high salt intake in wild-type mice significantly increased blood pressure and urinary albumin excretion and decreased plasma potassium concentrations, and these effects of aldosterone/salt were not affected by ASK1 deficiency. Thus, ASK1 seems to play a minor role in aldosterone-induced hypertension and renal injury. ASK1 deficiency also failed to affect aldosterone-induced cardiac hypertrophy. However, ASK1 deficiency markedly ameliorated aldosterone-induced cardiac injury, eg, the enhancement of cardiac macrophage infiltration, monocyte chemotactic protein 1 expression, interstitial fibrosis, perivascular fibrosis, and transforming growth factor-beta 1 and collagen type I expressions. Thus, ASK1 participates in aldosterone-induced cardiac inflammation and fibrosis. Furthermore, the enhancement of NADPH oxidase-mediated cardiac oxidative stress caused by aldosterone infusion was markedly lessened by ASK1 deficiency, which was associated with the significant amelioration by ASK1 deficiency of aldosterone-induced cardiac Nox2 upregulation. Furthermore, aldosterone/salt treatment significantly enhanced cardiac expression of the angiotensin-converting enzyme and angiotensin II type 1 receptor in wild-type mice, whereas the enhancement of these proteins by aldosterone/salt was abolished by ASK1 deficiency. Our results demonstrate that ASK1 is implicated in aldosterone/salt-induced cardiac inflammation and fibrosis through the enhancement of NADPH oxidase-mediated oxidative stress and the upregulation of the cardiac renin-angiotensin system. (Hypertension. 2009; 54: 544-551).