Paradoxical mineralocorticoid receptor activation and left ventricular diastolic dysfunction under high oxidative stress conditions
Paradoxical mineralocorticoid receptor activation and left ventricular diastolic dysfunction under high oxidative stress conditions
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DOI：
10.1097/hjh.0b013e328300a232
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发表时间：
2008-07
影响因子：
4.9
通讯作者：
Hong Wang;T. Shimosawa;Hiromitsu Matsui;Tomoyo Kaneko;S. Ogura;Y. Uetake;K. Takenaka;Y. Yatomi;T. Fujita
中科院分区：
文献类型：
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作者：
Hong Wang;T. Shimosawa;Hiromitsu Matsui;Tomoyo Kaneko;S. Ogura;Y. Uetake;K. Takenaka;Y. Yatomi;T. Fujita
背景盐状态通过调节活性氧的状态在血管紧张素II诱导的器官损伤中起关键作用，并且有报道活性氧激活盐皮质激素受体。方法为了阐明活性氧相关盐皮质激素受体激活在血管紧张素II诱导的心功能不全中的作用，我们研究了以下因素的影响：盐状态; MR拮抗剂依普利酮;和抗氧化剂tempol在血管紧张素II加载的Sprague-Dawley大鼠中。结果血管紧张素II/盐负荷使血压升高，依普利酮和tempol均不能显著拮抗血压升高。通过超声心动图或心导管术测量二尖瓣早期流入的峰值速度（E）、二尖瓣早期流入与心房收缩相关流量的比值（E/A）、二尖瓣早期流入的减速时间和−dP/dt、时间常数（T）和充盈压（左心室舒张末期压）来监测左心室舒张功能。尽管血清醛固酮被抑制，但血管紧张素II/高盐组左室舒张功能恶化，而血管紧张素II/低盐组不受影响。然而，血管紧张素-II/盐诱导的心功能不全的依普利酮和tempol恢复。烟酰胺腺嘌呤二核苷酸磷酸氧化酶衍生的超氧化物的形成是更大的血管紧张素II/高盐大鼠的心脏比血管紧张素II/低盐大鼠。Na+-H+交换亚型1的表达，盐皮质激素受体激活的目标，显着增加血管紧张素II/高盐组。Tempol和依普利酮均抑制血管紧张素II/盐诱导的Na+-H+交换器亚型1的上调。结论氧化应激激活盐皮质激素受体可导致轻度高血压大鼠左室舒张功能障碍。
Background Salt status plays a pivotal role in angiotensin-II-induced organ damage by regulating reactive oxygen species status, and it is reported that reactive oxygen species activate mineralocorticoid receptors. Method To clarify the role of reactive oxygen species-related mineralocorticoid receptor activation in angiotensin-II-induced cardiac dysfunction, we examined the effect of the following: salt status; an MR antagonist, eplerenone; and an antioxidant, tempol in angiotensin-II-loaded Sprague–Dawley rats. Results Angiotensin-II/salt-loading elevated blood pressure, and neither eplerenone nor tempol antagonized the rise in blood pressure significantly. Left ventricular diastolic function was monitored by measuring peak velocity of a mitral early inflow (E), the ratio of mitral early inflow to atrial contraction related flow (E/A), deceleration time of mitral early inflow and −dP/dt, the time constant (T), and filling pressure (left ventricular end-diastolic pressure) by echocardiography or cardiac catheterization. Despite the suppressed serum aldosterone, left ventricular diastolic function was deteriorated with angiotensin II/high salt, but not affected by angiotensin II/low salt. However, angiotensin-II/salt-induced cardiac dysfunction was restored by eplerenone and tempol. Nicotinamide adenine dinucleotide phosphateoxidase-derived superoxide formation was greater in the hearts of the angiotensin II/high-salt rats than of the angiotensin II/low-salt rats. The expression of the Na+–H+ exchanger isoform 1, a target of mineralocorticoid receptor activation, was significantly increased in the angiotensin II/high-salt group. Both tempol and eplerenone inhibited the angiotensin-II/salt-induced upregulation of Na+–H+ exchanger isoform 1. Conclusion These findings demonstrate that mineralocorticoid receptor activation by oxidative stress can cause left ventricular diastolic dysfunction in a rat model of mild hypertension.