Li Ying, Arnold J Malcolm O, Pampillo Macarena, Babwah Andy V, Peng Tianqing
Lawson Health Research Institute, Department of Medicine, University of Western Ontario, London, Canada.
Free Radic Biol Med. 2009 Jan 1;46(1):51-61. doi: 10.1016/j.freeradbiomed.2008.09.025. Epub 2008 Oct 9.
Taurine has been shown to prevent cardiomyocyte apoptosis. This study investigated the effects of taurine on NADPH oxidase and calpain activation in mediating apoptosis in cardiomyocytes. Apoptosis was induced by norepinephrine (NE) in cultured adult rat ventricular cardiomyocytes. NE (5 microM) increased NADPH oxidase activation and reactive oxygen species (ROS) production and induced apoptosis. These effects of NE on cardiomyocytes were diminished by taurine (0.5 mg/kg) but not beta-alanine. Inhibition of gp91(phox)-NADPH oxidase or ROS production protected cardiomyocytes from apoptosis. NE also induced calpain-1 activation in cardiomyocytes. This effect of NE on calpain was abrogated by gp91(phox)-NADPH oxidase inhibition or ROS scavengers and was mimicked by H(2)O(2) (25 microM) in cardiomyocytes. Pharmacological inhibitors of calpain or overexpression of calpastatin, a specific calpain inhibitor, blocked calpain activation and prevented cardiomyocyte apoptosis during NE stimulation. Furthermore, taurine treatment inhibited NE- or H(2)O(2)-induced calpain activation in cardiomyocytes. In conclusion, NADPH oxidase induces calpain activation, leading to apoptosis in NE-induced cardiomyocytes. Taurine inhibits NADPH oxidase and calpain activation. Thus, inhibition of NADPH oxidase-mediated calpain activation may be an important mechanism for taurine's antiapoptotic action in cardiomyocytes.
牛磺酸已被证明可预防心肌细胞凋亡。本研究调查了牛磺酸对烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶和钙蛋白酶激活在介导心肌细胞凋亡中的作用。在培养的成年大鼠心室心肌细胞中，去甲肾上腺素（NE）诱导细胞凋亡。NE（5微摩尔）增加了NADPH氧化酶的激活和活性氧（ROS）的产生，并诱导了细胞凋亡。牛磺酸（0.5毫克/千克）可减弱NE对心肌细胞的这些作用，但β-丙氨酸则无此作用。抑制gp91（phox）-NADPH氧化酶或ROS的产生可保护心肌细胞免于凋亡。NE还诱导心肌细胞中钙蛋白酶-1的激活。NE对钙蛋白酶的这种作用可被gp91（phox）-NADPH氧化酶抑制或ROS清除剂消除，并且在心肌细胞中可被过氧化氢（H₂O₂，25微摩尔）模拟。钙蛋白酶的药理学抑制剂或钙蛋白酶抑制蛋白（一种特异性钙蛋白酶抑制剂）的过表达可阻断钙蛋白酶的激活，并在NE刺激期间预防心肌细胞凋亡。此外，牛磺酸处理可抑制NE或H₂O₂诱导的心肌细胞中钙蛋白酶的激活。总之，NADPH氧化酶诱导钙蛋白酶激活，导致NE诱导的心肌细胞凋亡。牛磺酸抑制NADPH氧化酶和钙蛋白酶激活。因此，抑制NADPH氧化酶介导的钙蛋白酶激活可能是牛磺酸在心肌细胞中抗凋亡作用的重要机制。
