Cardiology Division, Phoenix VA Healthcare System, 650 E Indian School Rd, 111F, Phoenix, USA.
Norton Thoracic Institute, Phoenix, USA.
Apoptosis. 2019 Jun;24(5-6):395-403. doi: 10.1007/s10495-018-01510-y.
Lipoapoptosis of cardiomyocytes may underlie diabetic cardiomyopathy. Numerous forms of cardiomyopathies share a common end-pathway in which apoptotic loss of cardiomyocytes is mediated by p38α mitogen activated protein kinase (MAPK). Although we have previously shown that palmitic acid (PA), a saturated fatty acid (SFA) elevated in plasma of type 2 diabetes mellitus and morbid obesity, induces apoptosis in cardiomyocytes via p38α MAPK-dependent signaling, the downstream cascade events that cause cell death remain unknown. The objective of this study was to investigate mechanisms involved in palmitic acid-induced cardiomyocyte apoptosis. Human adult ventricular cardiomyocyte line (AC16 cells) exposed to high physiological levels of PA for 16 h showed enhanced transcription and phosphorylation of c-fos and c-jun subunits of AP-1 and transcription of caspase 8. When AC16 cells were transfected with small interfering RNA specific against p38α MAPK (si-p38α) for 24 or 48 h, the amplified phosphorylation of c-fos was dose-dependently attenuated, and procaspase 8 was dose-dependently reduced. With translational knockdown of c-fos, PA-induced apoptosis was diminished. Inhibition of caspase 8 for 24 h reduced apoptosis in PA-treated cardiomyocytes. These findings provide evidence for induction of apoptosis in cardiomyocytes exposed to high SFA by a novel pathway requiring activation of c-fos/AP-1 and caspase 8. These results demonstrate how elevated plasma SFA may lead to continual and cumulative loss of cardiomyocytes and potentially contribute to the development of diabetic cardiomyopathy.
心肌细胞的脂肪凋亡可能是糖尿病心肌病的基础。许多形式的心肌病都有一个共同的终末途径，即凋亡性心肌细胞丢失是由 p38α 有丝分裂原激活蛋白激酶（MAPK）介导的。虽然我们之前已经表明，在 2 型糖尿病和病态肥胖患者血浆中升高的饱和脂肪酸（SFA）棕榈酸（PA）通过 p38α MAPK 依赖性信号诱导心肌细胞凋亡，但导致细胞死亡的下游级联事件尚不清楚。本研究的目的是研究与 PA 诱导的心肌细胞凋亡相关的机制。在生理水平的 PA 作用 16 小时后，暴露于高生理水平 PA 的人心室肌细胞系（AC16 细胞）显示出 c-fos 和 c-jun 亚基的 AP-1 和 caspase 8 的转录和磷酸化增强。当 AC16 细胞用针对 p38α MAPK 的小干扰 RNA（si-p38α）转染 24 或 48 小时时，c-fos 的磷酸化被剂量依赖性地减弱，而 procaspase 8 被剂量依赖性地减少。用 c-fos 的翻译抑制，PA 诱导的凋亡减少。在 caspase 8 抑制 24 小时后，PA 处理的心肌细胞中的凋亡减少。这些发现为高 SFA 暴露的心肌细胞诱导凋亡提供了证据，该途径需要激活 c-fos/AP-1 和 caspase 8。这些结果表明，血浆 SFA 水平升高如何导致心肌细胞的持续和累积丢失，并可能导致糖尿病心肌病的发展。
