Campos Erica C, Romano Minna M D, Prado Cibele M, Rossi Marcos A
Department of Pathology (Cellular and Molecular Cardiology), Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.
Int J Exp Pathol. 2008 Oct;89(5):367-81. doi: 10.1111/j.1365-2613.2008.00604.x.
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, beta1-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.
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活动亢进后氧供需不匹配是对所观察到的复杂形态学改变的最佳解释。已证明异丙肾上腺素可导致心肌细胞肌膜结构完整性的严重改变。考虑到肌膜完整性由肌营养不良蛋白-糖蛋白复合物（DGC）稳定，该复合物在收缩机制和细胞外基质中连接肌动蛋白和层粘连蛋白，并且由整合素稳定，本研究检验了异丙肾上腺素通过DGC和整合素的变化影响肌膜稳定性的假说。我们发现DGC和整合素对皮下注射异丙肾上腺素具有不同的敏感性。免疫荧光染色显示，在连接心肌细胞骨架中的肌动蛋白和细胞外基质的结构中，肌营养不良蛋白最敏感。肌营养不良蛋白减少或缺失后，肌节肌动蛋白溶解。随后，在肌丝溶解后，γ-肌聚糖、β-肌营养不良聚糖、β1-整合素和层粘连蛋白α-2的表达降低，随后它们分解，这是肌细胞溶解过程的附带现象。总之，给大鼠注射异丙肾上腺素会导致肌营养不良蛋白的原发性丧失，肌营养不良蛋白是形成连接心肌细胞细胞外基质和细胞骨架的DGC的结构蛋白中最敏感的。这些与缺血性损伤相关的变化解释了心肌细胞肌膜结构完整性的严重改变，从而解释了异丙肾上腺素诱导的严重且不可逆的损伤。
