Endothelin-1 mediates cardiac mast cell degranulation, matrix metalloproteinase activation, and myocardial remodeling in rats
Endothelin-1 mediates cardiac mast cell degranulation, matrix metalloproteinase activation, and myocardial remodeling in rats
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DOI：
10.1152/ajpheart.00048.2004
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发表时间：
2004-11-01
影响因子：
4.8
通讯作者：
Janicki, JS
中科院分区：
文献类型：
--
作者：
Murray, DB;Gardner, JD;Janicki, JS
本研究的目的是确定是否升高的内皮素（ET）-1循环水平能够介导左心室（LV）肥大细胞脱颗粒，从而诱导基质金属蛋白酶（MMP）激活。在给予20 μ g/ml ET-1至血液灌注的离体大鼠心脏后，分析LV组织中肥大细胞脱粒和MMP活化的迹象。与对照组相比，ET-1引起肥大细胞广泛脱颗粒，心肌含水量显著增加（78.8 ± 1.5% vs. 74.2 ± 2.2%，P < 0.01），MMP-2活性显著增加107（P < 0.05），胶原体积分数显著降低（0.69 +/- 0.09%对0.99 +/-0.04%，P < 0.001）。尽管预期心肌水肿会增加心室僵硬度，但顺应性未改变，并观察到中度心室扩张（舒张末期压为0 mmHg时，ET-1治疗组与对照组的舒张末期容积分别为330.2 ± 22.1 vs. 298.9 ± 17.4 μl，P = 0.07）。此外，用肥大细胞稳定剂奈多罗米预处理可防止ET-1诱导的MMP-2活性、心肌含水量、胶原体积分数和舒张末期容积的变化。这些结果表明，ET-1是一种有效的心脏肥大细胞促分泌剂，并进一步表明，ET-1介导的肥大细胞脱颗粒是一个潜在的机制，负责心肌重塑。
The objective of this study was to determine whether elevated circulating levels of endothelin (ET)-1 are capable of mediating left ventricular (LV) mast cell degranulation and thereby induce matrix metalloproteinase (MMP) activation. After the administration of 20 pg/ml ET-1 to blood-perfused isolated rat hearts, LV tissue was analyzed for signs of mast cell degranulation and MMP activation. Relative to control, ET-1 produced extensive mast cell degranulation as well as a significant increase in myocardial water content (78.8 +/- 1.5% vs. 74.2 +/- 2.2%, P < 0.01), a marked 107% increase in MMP-2 activity (P < 0.05), and a substantial decrease in collagen volume fraction (0.69 +/- 0.09% vs. 0.99 +/- 0.04%, P < 0.001). Although the myocardial edema would be expected to increase ventricular stiffness, compliance was not altered, and moderate ventricular dilatation was observed (end-diastolic volume at end-diastolic pressure of 0 mmHg of 330.2 ± 22.1 vs. 298.9 ± 17.4 μl in ET-1 treated vs. control, respectively, P = 0.07). Additionally, pretreatment with the mast cell stabilizer nedocromil prevented ET-1-induced changes in MMP-2 activity, myocardial water content, collagen volume fraction, and end-diastolic volume. These findings demonstrate that ET-1 is a potent cardiac mast cell secretogogue and further indicate that ET-1-mediated mast cell degranulation is a potential mechanism responsible for myocardial remodeling.