Involvement of RhoA/Rho kinase signaling in protection against monocrotaline-induced pulmonary hypertension in pneumonectomized rats by dehydroepiandrosterone
Involvement of RhoA/Rho kinase signaling in protection against monocrotaline-induced pulmonary hypertension in pneumonectomized rats by dehydroepiandrosterone
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DOI：
10.1152/ajplung.90251.2008
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发表时间：
2008-07-01
影响因子：
4.9
通讯作者：
Oka, Masahiko
中科院分区：
文献类型：
--
作者：
Homma, Noriyuki;Nagaoka, Tetsutaro;Oka, Masahiko
RhoA/Rho激酶（ROCK）信号在实验性肺动脉高压（PH）的发病机制中起关键作用。脱氢表雄酮（DHEA）是一种天然存在的类固醇激素，可有效抑制慢性缺氧PH，但其机制尚不清楚。本研究检测了脱氢表雄酮是否对MCT诱导的左肺切除大鼠的PH值也有效，以及脱氢表雄酮的保护作用是否与RhoA/ROCK信号的抑制有关。注射MCT后3周，肺切除大鼠出现PH伴严重血管重构，包括肺小动脉闭塞性内膜病变。在这些动物的肺中，我们检测到裂解（组成活性）ROCK I， RhoA和ROCK活性增加，ROCK II蛋白表达增加。慢性脱氢表雄酮治疗（1%，通过食物治疗3周）显著抑制mct诱导的肺切除大鼠PH（0%和1%脱氢表雄酮治疗后的平均肺动脉压分别为33 +/- 5和16 +/- 1 mmHg）和严重的肺血管重塑。mct诱导的RhoA/ rock相关蛋白表达变化几乎被脱氢表雄酮正常化。在注射MCT 3周后开始3周的DHEA治疗（1%），完全抑制了PH的进展（0%和1% DHEA治疗后的平均肺动脉压分别为47 +/- 3和30 +/- 3 mmHg），这种治疗也导致100%的存活率，而未经DHEA治疗的大鼠的存活率为30%。这些结果表明，抑制RhoA/ROCK信号，包括ROCK I的裂解和组成性激活，是DHEA对mct诱导的肺切除大鼠PH的显著保护作用的重要组成部分。
RhoA/Rho kinase (ROCK) signaling plays a key role in the pathogenesis of experimental pulmonary hypertension (PH). Dehydroepiandrosterone (DHEA), a naturally occurring steroid hormone, effectively inhibits chronic hypoxic PH, but the responsible mechanisms are unclear. This study tested whether DHEA was also effective in treating monocrotaline (MCT)-induced PH in left pneumonectomized rats and whether inhibition of RhoA/ROCK signaling was involved in the protective effect of DHEA. Three weeks after MCT injection, pneumonectomized rats developed PH with severe vascular remodeling, including occlusive neointimal lesions in pulmonary arterioles. In lungs from these animals, we detected cleaved (constitutively active) ROCK I as well as increases in activities of RhoA and ROCK and increases in ROCK II protein expression. Chronic DHEA treatment (1%, by food for 3 wk) markedly inhibited the MCT-induced PH (mean pulmonary artery pressures after treatment with 0% and 1% DHEA were 33 +/- 5 and 16 +/- 1 mmHg, respectively) and severe pulmonary vascular remodeling in pneumonectomized rats. The MCT-induced changes in RhoA/ROCK-related protein expression were nearly normalized by DHEA. A 3-wk DHEA treatment (1%) started 3 wk after MCT injection completely inhibited the progression of PH (mean pulmonary artery pressures after treatment with 0% and 1% DHEA were 47 +/- 3 and 30 +/- 3 mmHg, respectively), and this treatment also resulted in 100% survival in contrast to 30% in DHEA-untreated rats. These results suggest that inhibition of RhoA/ROCK signaling, including the cleavage and constitutive activation of ROCK I, is an important component of the impressive protection of DHEA against MCT-induced PH in pneumonectomized rats.