Isoproterenol induces primary loss of dystrophin in rat hearts: correlation with myocardial injury
Isoproterenol induces primary loss of dystrophin in rat hearts: correlation with myocardial injury
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DOI：
10.1111/j.1365-2613.2008.00604.x
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发表时间：
2008-10-01
影响因子：
3
通讯作者：
Rossi, Marcos A.
中科院分区：
文献类型：
--
作者：
Campos, Erica C.;Romano, Minna M. D.;Rossi, Marcos A.
异丙肾上腺素诱导心肌损伤的机制尚不清楚，但冠状动脉低血压和心肌亢进后的氧供应与需求不匹配是观察到的复杂形态学改变的最佳解释。心肌细胞肌膜结构完整性的严重改变已被证明是由异丙肾上腺素引起的。考虑到肌萎缩蛋白-糖蛋白复合物（dystrophin-glycoprotein complex， DGC）在收缩机制和细胞外基质中连接肌动蛋白和层粘连蛋白，并通过整合素来稳定肌上皮的完整性，本研究验证了异丙肾上腺素通过改变DGC和整合素来影响肌上皮稳定性的假设。我们发现DGC和整合素对异丙肾上腺素皮下给药的敏感性不同。免疫荧光染色显示，在连接肌动蛋白的心肌细胞骨架和细胞外基质的结构中，肌营养不良蛋白是最敏感的。肌动蛋白溶解发生在肌营养不良蛋白减少或丧失之后。随后，在肌丝溶解后，-肌聚糖、-肌营养不良聚糖、- 1-整合素和层粘连蛋白α -2的表达减少，随后它们被分解，作为肌细胞溶解过程的副现象。综上所述，大鼠服用异丙肾上腺素会导致肌营养不良蛋白的原发性缺失，而肌营养不良蛋白是构成心肌细胞中连接细胞外基质和细胞骨架的DGC的最敏感的结构蛋白。这些变化与缺血性损伤有关，解释了心肌细胞肌膜结构完整性的严重改变，因此异丙肾上腺素引起了严重和不可逆的损伤。
The mechanism of isoproterenol-induced myocardial damage is unknown, but a mismatch of oxygen supply vs. demand following coronary hypotension and myocardial hyperactivity is the best explanation for the complex morphological alterations observed. Severe alterations in the structural integrity of the sarcolemma of cardiomyocytes have been demonstrated to be caused by isoproterenol. Taking into account that the sarcolemmal integrity is stabilized by the dystrophin-glycoprotein complex (DGC) that connects actin and laminin in contractile machinery and extracellular matrix and by integrins, this study tests the hypothesis that isoproterenol affects sarcolemmal stability through changes in the DGC and integrins. We found different sensitivity of the DGC and integrin to isoproterenol subcutaneous administration. Immunofluorescent staining revealed that dystrophin is the most sensitive among the structures connecting the actin in the cardiomyocyte cytoskeleton and the extracellular matrix. The sarcomeric actin dissolution occurred after the reduction or loss of dystrophin. Subsequently, after lysis of myofilaments, gamma-sarcoglycan, beta-dystroglycan, beta 1-integrin, and laminin alpha-2 expressions were reduced followed by their breakdown, as epiphenomena of the myocytolytic process. In conclusion, administration of isoproterenol to rats results in primary loss of dystrophin, the most sensitive among the structural proteins that form the DGC that connects the extracellular matrix and the cytoskeleton in cardiomyocyte. These changes, related to ischaemic injury, explain the severe alterations in the structural integrity of the sarcolemma of cardiomyocytes and hence severe and irreversible injury induced by isoproterenol.