Spironolactone Decreases Isoproterenol-Induced Ventricular Fibrosis and Matrix Metalloproteinase-2 in Rats
Spironolactone Decreases Isoproterenol-Induced Ventricular Fibrosis and Matrix Metalloproteinase-2 in Rats
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DOI：
10.1248/bpb.34.61
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发表时间：
2011-01-01
影响因子：
2
通讯作者：
Higuchi, Sei-ichi
中科院分区：
文献类型：
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作者：
Hori, Yasutomo;Yoshioka, Kazuki;Higuchi, Sei-ichi
虽然已经报道了交感神经系统和肾素-血管紧张素-醛固酮系统之间的反式调节，但交感神经活性亢进诱导的基质金属蛋白酶（MMP）表达/活性和心脏纤维化是否由盐皮质激素受体系统介导仍不清楚。我们研究了异丙肾上腺素（ISO）诱导的NIMP表达/活性和心脏纤维化是否由螺内酯介导。雄性Wistar京都大鼠分为对照组、ISO组和ISO+螺内酯组。ISO（2.0 mg/kg/d）和SPI（40 mg/kg/d）灌胃14 d。记录超声心动图和血流动力学测量结果，并切除心脏。通过组织病理学分析评估肌细胞横截面和纤维化面积。MMP-2和胶原-I通过Western印迹和酶谱分析。与对照组相比，ISO显著升高舒张末期左心室（LV）压力和等容舒张时间常数，降低-dP/dt，而SPI联合治疗没有。ISO处理诱导的缩短分数和相对壁厚显着增加，而SPI共处理显着降低相对壁厚。类似地，ISO显著增加LV重量和肌细胞横截面积和纤维化面积，这与MMP-2表达/活性和I型胶原表达同时发生。此外，ISO诱导的这些功能被SPI共处理显著减弱。我们的研究结果表明，ISO诱发的交感神经功能亢进导致LV纤维化和MMP-2，这可能是通过盐皮质激素受体系统部分控制。
Although transregulation between the sympathetic nervous system and the renin-angiotensin-aldosterone system has been reported, it remains unclear whether sympathetic hyperactivity-induced matrix metalloproteinease (MMP) expression/activity and cardiac fibrosis are mediated by the mineralocorticoid receptor system. We investigated whether isoproterenol (ISO)-induced NIMP expression/activity and cardiac fibrosis are mediated by spironolactone in rats. Male Wistar Kyoto rats were divided into 3 groups: control, ISO, and ISO combined with spironolactone (SPI). ISO (2.0 mg/kg/d) and/or SPI (40 mg/kg/d) were given for 14 d. Echocardiography and hemodynamic measurements were recorded and hearts were excised. The myocyte cross-sectional and fibrotic area was evaluated via histopathological analysis. MMP-2 and collagen-I were analyzed by Western blotting and zymography. Compared with the controls, ISO significantly elevated the end-diastolic left ventricular (LV) pressure and the time constant of isovolumic relaxation and decreased the -dP/dt, while those of SPI co-treatment did not. ISO treatment induced significant increases in the fractional shortening and relative wall thickness, whereas SPI co-treatment significantly decreased relative wall thickness. Similarly, ISO significantly increased LV weight and myocyte cross-sectional and fibrotic area, which occurred concomitantly with the MMP-2 expression/activity and the expression of collagen-I. Moreover, ISO induced these features were significantly attenuated by SPI co-treatment. Our results suggest that ISO-evoked sympathetic hyperactivity induced LV fibrosis and MMP-2, which may be partially controlled via the mineralocorticoid receptor system.