Nakamura Taishi, Kataoka Keiichiro, Fukuda Masaya, Nako Hisato, Tokutomi Yoshiko, Dong Yi-Fei, Ichijo Hidenori, Ogawa Hisao, Kim-Mitsuyama Shokei
Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjyo, Kumamoto 860-8556, Japan.
Hypertension. 2009 Sep;54(3):544-51. doi: 10.1161/HYPERTENSIONAHA.109.135392. Epub 2009 Jul 6.
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-beta1 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.
醛固酮/盐诱导的心血管损伤的分子机制仍有待确定。本研究旨在确定凋亡信号调节激酶1（ASK1）在醛固酮诱导的体内心脏损伤机制中的作用。我们比较了醛固酮/盐处理4周对野生型和ASK1缺陷型小鼠的体内影响。野生型小鼠输注醛固酮加高盐摄入显著升高血压、增加尿白蛋白排泄并降低血浆钾浓度，醛固酮/盐的这些作用不受ASK1缺陷的影响。因此，ASK1似乎在醛固酮诱导的高血压和肾损伤中起次要作用。ASK1缺陷也未影响醛固酮诱导的心脏肥大。然而，ASK1缺陷显著改善了醛固酮诱导的心脏损伤，例如，心脏巨噬细胞浸润增强、单核细胞趋化蛋白1表达、间质纤维化、血管周围纤维化以及转化生长因子-β1和I型胶原表达增强。因此，ASK1参与醛固酮诱导的心脏炎症和纤维化。此外，ASK1缺陷显著减轻了醛固酮输注引起的NADPH氧化酶介导的心脏氧化应激增强，这与ASK1缺陷显著改善醛固酮诱导的心脏Nox2上调有关。此外，醛固酮/盐处理显著增强了野生型小鼠心脏中血管紧张素转换酶和血管紧张素II 1型受体的表达，而醛固酮/盐对这些蛋白的增强作用被ASK1缺陷所消除。我们的结果表明，ASK1通过增强NADPH氧化酶介导的氧化应激和心脏肾素-血管紧张素系统的上调，参与醛固酮/盐诱导的心脏炎症和纤维化。
