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首页> 外文期刊>American Journal of Physiology >Tumor necrosis factor-alpha in mechanic trauma plasma mediates cardiomyocyte apoptosis.
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Tumor necrosis factor-alpha in mechanic trauma plasma mediates cardiomyocyte apoptosis.

机译：机械损伤血浆中的肿瘤坏死因子-α介导心肌细胞凋亡。

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Mechanical traumatic injury causes cardiomyocyte apoptosis and cardiac dysfunction. However, the signaling mechanisms leading to posttraumatic cardiomyocyte apoptosis remains unclear. The present study attempted to identify the molecular mechanisms responsible for cardiomyocyte apoptosis induced by trauma. Normal cardiomyocytes (NC) or traumatic cardiomyocytes (TC; isolated immediately after trauma) were cultured with normal plasma (NP) or traumatic plasma (TP; isolated 1.5 h after trauma) for 12 h, and apoptosis was determined by caspase-3 activation. Exposure of TC to NP failed to induce significant cardiomyocyte apoptosis. In contrast, exposure of NC to TP resulted in a greater than twofold increase in caspase-3 activation (P < 0.01). Incubation of cardiomyocytes with cytomix (a mixture of TNF-alpha, IL-1beta, and IFN-gamma) or TNF-alpha alone, but not with IL-1beta or IFN-gamma alone, caused significant caspase-3 activation (P < 0.01). TP-induced caspase-3 activation was virtually abolished by an anti-TNF-alpha antibody, and TP isolated from TNF-alpha(-/-) mice failed to induce caspase-3 activation. Moreover, incubation of cardiomyocytes with TP upregulated inducible nitric oxide (NO) synthase (iNOS)/NADPH oxidase expression, increased NO/superoxide production, and increased cardiomyocyte protein nitration (measured by nitrotyrosine content). These oxidativeitrative stresses and the resultant cardiomyocyte caspase-3 activation can be blocked by neutralization of TNF-alpha (anti-TNF-alpha antibody), inhibition of iNOS (1400W), or NADPH oxidase (apocynin) and scavenging of peroxynitrite (FP15) (P < 0.01). Taken together, our study demonstrated that there exists a TNF-alpha-initiated, cardiomyocyte iNOS/NADPH oxidase-dependent, peroxynitrite-mediated signaling pathway that contributes to posttraumatic myocardial apoptosis. Therapeutic interventions that block this signaling cascade may attenuate posttraumatic cardiac injury and reduce the incidence of secondary organ dysfunction after trauma.
机译：机械性外伤导致心肌细胞凋亡和心脏功能障碍。然而，导致创伤后心肌细胞凋亡的信号传导机制仍不清楚。本研究试图确定造成创伤引起的心肌细胞凋亡的分子机制。正常心肌细胞（NC）或创伤性心肌细胞（TC;在创伤后立即分离）与正常血浆（NP）或创伤性血浆（TP;在创伤后1.5 h分离）培养12 h，并通过caspase-3激活测定细胞凋亡。 TC暴露于NP未能诱导明显的心肌细胞凋亡。相反，NC暴露于TP导致caspase-3激活增加了两倍以上（P <0.01）。单独用cytomix（TNF-α，IL-1beta和IFN-γ的混合物）或TNF-alpha孵育心肌细胞，但不单独用IL-1beta或IFN-γ孵育，则导致caspase-3活化显着（P <0.01 ）。 TP诱导的caspase-3激活实际上被一种抗TNF-α抗体废除了，从TNF-alpha（-/-）小鼠分离的TP无法诱导caspase-3激活。此外，用TP孵育心肌细胞会上调可诱导型一氧化氮（NO）合酶（iNOS）/ NADPH氧化酶的表达，增加NO /超氧化物的产生，并增加心肌蛋白的硝化作用（通过硝基酪氨酸含量来衡量）。可通过中和TNF-α（抗TNF-α抗体），抑制iNOS（1400W）或NADPH氧化酶（阿波西宁）和清除过氧亚硝酸盐（FP15）来阻止这些氧化/氧化应激以及由此产生的心肌caspase-3激活。 ）（P <0.01）。两者合计，我们的研究表明，存在一种由TNF-α引发的心肌细胞iNOS / NADPH氧化酶依赖性过氧亚硝酸盐介导的信号通路，其有助于创伤后心肌细胞凋亡。阻断这种信号传导级联的治疗性干预措施可以减轻创伤后心脏的损伤，并减少创伤后继发器官功能障碍的发生率。

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