Endowed Chair in Cardiology and Vascular Medicine, School of Medicine, Tecnológico de Monterrey, Monterrey México;
Endowed Chair in Cardiology and Vascular Medicine, School of Medicine, Tecnológico de Monterrey, Monterrey México; Basic and Translational Research Center, Hospital Zambrano-Hellion, TEC Salud, San Pedro, Garza-García, México; and.
Am J Physiol Heart Circ Physiol. 2015 Mar 1;308(5):H467-77. doi: 10.1152/ajpheart.00734.2013. Epub 2014 Dec 19.
Stress-induced cardiomyopathy, triggered by acute catecholamine discharge, is a syndrome characterized by transient, apical ballooning linked to acute heart failure and ventricular arrhythmias. Rats receiving an acute isoproterenol (ISO) overdose (OV) suffer cardiac apex ischemia-reperfusion damage and arrhythmia, and then undergo cardiac remodeling and dysfunction. Nevertheless, the subcellular mechanisms underlying cardiac dysfunction after acute damage subsides are not thoroughly understood. To address this question, Wistar rats received a single ISO injection (67 mg/kg). We found in vivo moderate systolic and diastolic dysfunction at 2 wk post-ISO-OV; however, systolic dysfunction recovered after 4 wk, while diastolic dysfunction worsened. At 2 wk post-ISO-OV, cardiac function was assessed ex vivo, while mitochondrial oxidative metabolism and stress were assessed in vitro, and Ca(2+) handling in ventricular myocytes. These were complemented with sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA), phospholamban (PLB), and RyR2 expression studies. Ex vivo, basal mechanical performance index (MPI) and oxygen consumption rate (MVO2) were unchanged. Nevertheless, upon increase of metabolic demand, by β-adrenergic stimulation (1-100 nM ISO), the MPI versus MVO2 relation decreased and shifted to the right, suggesting MPI and mitochondrial energy production uncoupling. Mitochondria showed decreased oxidative metabolism, membrane fragility, and enhanced oxidative stress. Myocytes presented systolic and diastolic Ca(2+) mishandling, and blunted response to ISO (100 nM), and all these without apparent changes in SERCA, PLB, or RyR2 expression. We suggest that post-ISO-OV mitochondrial dysfunction may underlie decreased cardiac contractility, mainly by depletion of ATP needed for myofilaments and Ca(2+) transport by SERCA, while exacerbated oxidative stress may enhance diastolic RyR2 activity.
应激性心肌病，由急性儿茶酚胺释放触发，是一种综合征，其特征为短暂性、心尖球囊样变与急性心力衰竭和室性心律失常相关。接受急性异丙肾上腺素（ISO）过量（OV）的大鼠发生心脏心尖缺血-再灌注损伤和心律失常，随后发生心脏重构和功能障碍。然而，急性损伤消退后心脏功能障碍的亚细胞机制尚不清楚。为了解决这个问题，Wistar 大鼠接受单次 ISO 注射（67mg/kg）。我们发现 ISO-OV 后 2 周时体内存在中度收缩和舒张功能障碍；然而，4 周后收缩功能恢复，而舒张功能恶化。在 ISO-OV 后 2 周，进行离体心脏功能评估，同时评估体外线粒体氧化代谢和应激以及心室肌细胞 Ca(2+)处理。这些与肌浆网（内质网）Ca(2+)-ATP 酶（SERCA）、磷蛋白（PLB）和 RyR2 表达研究相结合。离体时，基础机械性能指数（MPI）和耗氧量（MVO2）不变。然而，当代谢需求增加时，通过β-肾上腺素刺激（1-100nM ISO），MPI 与 MVO2 的关系下降并向右移位，表明 MPI 和线粒体能量产生解偶联。线粒体显示氧化代谢减少、膜脆性增加和氧化应激增强。心肌细胞表现出收缩和舒张 Ca(2+)处理不当，对 ISO（100nM）的反应迟钝，所有这些都没有明显改变 SERCA、PLB 或 RyR2 的表达。我们认为 ISO-OV 后线粒体功能障碍可能是心脏收缩功能下降的基础，主要是由于肌球蛋白丝和 SERCA 转运 Ca(2+)所需的 ATP 耗尽，而加剧的氧化应激可能增强舒张期 RyR2 活性。
