ROLES OF OXIDATIVE STRESS AND THE MINERALOCORTICOID RECEPTOR IN CARDIAC PATHOLOGY IN A RAT MODEL OF METABOLIC SYNDROME
ROLES OF OXIDATIVE STRESS AND THE MINERALOCORTICOID RECEPTOR IN CARDIAC PATHOLOGY IN A RAT MODEL OF METABOLIC SYNDROME
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DOI：
10.18999/nagjms.77.1-2.275
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发表时间：
2015-02
影响因子：
0.9
通讯作者：
Keiji Takahashi;Tamayo Murase;Miwa Takatsu;Natsumi Matsuura;Kai Nagasawa;Takuya Hattori;Shogo Watanabe;T. Murohara;K. Nagata
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文献类型：
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作者：
Keiji Takahashi;Tamayo Murase;Miwa Takatsu;Natsumi Matsuura;Kai Nagasawa;Takuya Hattori;Shogo Watanabe;T. Murohara;K. Nagata
摘要：氧化应激和盐皮质激素受体 (MR) 与盐诱导的左心室 (LV) 舒张功能障碍（与代谢综合征 (MetS) 相关）的发病机制有关。我们最近将 DahlS.Z-Leprfa/Leprfa (DS/obese) 大鼠进行了表征，该大鼠源自 Dahl 盐敏感大鼠和 Zucker 大鼠的杂交，作为 MetS 的新动物模型。我们利用该模型研究了氧化应激增加和 MR 激活在心脏损伤中的病理生理学作用。 DS/肥胖大鼠从 10 周龄开始接受抗氧化剂 tempol（饮用水中 1 mmol/L）或选择性 MR 拮抗剂 eplerenone（每天 15 mg/kg，口服）治疗 5 周。未经治疗的 DS/肥胖大鼠中出现的收缩压升高和左心室肥厚可通过依普利农得到显着改善，但通过 tempol 则不能改善。在 DS/肥胖大鼠中，依普利酮还比 tempol 更有效地减轻左心室纤维化和舒张功能障碍，而两种药物都可以类似地减少心脏氧化应激和炎症。血浆醛固酮浓度与血浆肾素活性的比率以及 MR 和血清/糖皮质激素调节激酶 1 基因的心脏表达，依普利酮比 tempol 降低的程度更大。我们的结果表明，心脏氧化应激增加和 MR 激活可能导致 DS/肥胖大鼠左室重塑和舒张功能障碍的发生。依普利农卓越的心脏保护作用可能归因于其更强的抗高血压作用，这可能与其对心血管系统中醛固酮-MR活性的更大抑制有关。
ABSTRACT Oxidative stress and the mineralocorticoid receptor (MR) are implicated in the pathogenesis of salt-induced left ventricular (LV) diastolic dysfunction associated with metabolic syndrome (MetS). We recently characterized DahlS.Z-Leprfa/Leprfa (DS/obese) rats, derived from a cross between Dahl salt-sensitive and Zucker rats, as a new animal model of MetS. We investigated the pathophysiological roles of increased oxidative stress and MR activation in cardiac injury with this model. DS/obese rats were treated with the antioxidant tempol (1 mmol/L in drinking water) or the selective MR antagonist eplerenone (15 mg/kg per day, per os) for 5 weeks beginning at 10 weeks of age. The increased systolic blood pressure and LV hypertrophy that develop in untreated DS/obese rats were substantially ameliorated by eplerenone but not by tempol. Eplerenone also attenuated LV fibrosis and diastolic dysfunction more effectively than did tempol in DS/obese rats, whereas cardiac oxidative stress and inflammation were reduced similarly by both drugs. Both the ratio of plasma aldosterone concentration to plasma renin activity and cardiac expression of the MR and serum/glucocorticoid–regulated kinase 1 genes were decreased to a greater extent by eplerenone than by tempol. Our results indicate that both increased oxidative stress and MR activation in the heart may contribute to the development of LV remodeling and diastolic dysfunction in DS/obese rats. The superior cardioprotective action of eplerenone is likely attributable to its greater antihypertensive effect, which is likely related to its greater inhibition of aldosterone-MR activity in the cardiovascular system.