Ghosh Jyotirmoy, Das Joydeep, Manna Prasenjit, Sil Parames C
Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata-700054, West Bengal, India.
Toxicol Appl Pharmacol. 2009 Oct 1;240(1):73-87. doi: 10.1016/j.taap.2009.07.008. Epub 2009 Jul 17.
Cardiac dysfunction is a major cause of morbidity and mortality worldwide due to its complex pathogenesis. However, little is known about the mechanism of arsenic-induced cardiac abnormalities and the use of antioxidants as the possible protective agents in this pathophysiology. Conditionally essential amino acid, taurine, accounts for 25% to 50% of the amino acid pool in myocardium and possesses antioxidant properties. The present study has, therefore, been carried out to investigate the underlying mechanism of the beneficial role of taurine in arsenic-induced cardiac oxidative damage and cell death. Arsenic reduced cardiomyocyte viability, increased reactive oxygen species (ROS) production and intracellular calcium overload, and induced apoptotic cell death by mitochondrial dependent caspase-3 activation and poly-ADP ribose polymerase (PARP) cleavage. These changes due to arsenic exposure were found to be associated with increased IKK and NF-kappaB (p65) phosphorylation. Pre-exposure of myocytes to an IKK inhibitor (PS-1145) prevented As-induced caspase-3 and PARP cleavage. Arsenic also markedly increased the activity of p38 and JNK MAPKs, but not ERK to that extent. Pre-treatment with SP600125 (JNK inhibitor) and SB203580 (p38 MAPK inhibitor) attenuated NF-kappaB and IKK phosphorylation indicating that p38 and JNK MAPKs are mainly involved in arsenic-induced NF-kappaB activation. Taurine treatment suppressed these apoptotic actions, suggesting that its protective role in arsenic-induced cardiomyocyte apoptosis is mediated by attenuation of p38 and JNK MAPK signaling pathways. Similarly, arsenic intoxication altered a number of biomarkers related to cardiac oxidative stress and other apoptotic indices in vivo and taurine supplementation could reduce it. Results suggest that taurine prevented arsenic-induced myocardial pathophysiology, attenuated NF-kappaB activation via IKK, p38 and JNK MAPK signaling pathways and could possibly provide a protection against As-induced cardiovascular burden.
由于其复杂的发病机制，心脏功能障碍是全球发病和死亡的主要原因。然而，关于砷诱导的心脏异常机制以及抗氧化剂作为这种病理生理学中可能的保护剂的使用，人们知之甚少。条件必需氨基酸牛磺酸占心肌氨基酸池的25%至50%，并具有抗氧化特性。因此，本研究旨在探讨牛磺酸在砷诱导的心脏氧化损伤和细胞死亡中的有益作用的潜在机制。砷降低了心肌细胞活力，增加了活性氧（ROS）生成和细胞内钙超载，并通过线粒体依赖性半胱天冬酶-3激活和聚ADP核糖聚合酶（PARP）裂解诱导凋亡细胞死亡。发现这些由于砷暴露引起的变化与IKK和核因子-κB（p65）磷酸化增加有关。心肌细胞预先暴露于IKK抑制剂（PS-1145）可防止砷诱导的半胱天冬酶-3和PARP裂解。砷还显著增加了p38和JNK丝裂原活化蛋白激酶（MAPK）的活性，但对细胞外信号调节激酶（ERK）的增加程度没有那么大。用SP600125（JNK抑制剂）和SB203580（p38 MAPK抑制剂）预处理可减弱核因子-κB和IKK磷酸化，表明p38和JNK MAPK主要参与砷诱导的核因子-κB激活。牛磺酸处理抑制了这些凋亡作用，表明其在砷诱导的心肌细胞凋亡中的保护作用是通过减弱p38和JNK MAPK信号通路介导的。同样，砷中毒在体内改变了许多与心脏氧化应激和其他凋亡指标相关的生物标志物，补充牛磺酸可以降低这些指标。结果表明，牛磺酸可预防砷诱导的心肌病理生理学，通过IKK、p38和JNK MAPK信号通路减弱核因子-κB激活，并可能提供针对砷诱导的心血管负担的保护作用。
