A metabolic role for mitochondria in palmitate-induced cardiac myocyte apoptosis
A metabolic role for mitochondria in palmitate-induced cardiac myocyte apoptosis
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DOI：
10.1152/ajpheart.2000.279.5.h2124
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发表时间：
2000-11-01
影响因子：
4.8
通讯作者：
McMillin, JB
中科院分区：
文献类型：
--
作者：
Sparagna, GC;Hickson-Bick, DL;McMillin, JB
心脏缺血后，血浆和心脏中棕榈酸酯等长链脂肪酸增加。棕榈酸酯先前已被证明可引起心肌细胞凋亡。研究了培养的新生大鼠心肌细胞在凋亡过程中线粒体的改变。磷脂酰丝氨酸易位和caspase 3样活性证实了棕榈酸酯的凋亡作用。胞质细胞色素c在8小时检测到，12小时达到稳定水平。负载四甲基罗丹明乙基酯的心肌细胞的线粒体膜电位（Delta Psi）在8小时内显著降低。这种损失是不均匀的，每个心肌细胞在24小时内仍有少数充满能量的线粒体。总ATP水平在16小时保持高水平。环sporin a（一种线粒体通透性转变抑制剂）延迟了Delta Psi的损失。线粒体肿胀伴随着δ Psi的变化。肉碱棕榈酰基转移酶I活性在16 h时下降；这种下降伴随着神经酰胺的增加，与复合物III活性的下降相平行。我们得出结论，肉碱棕榈酰基转移酶I抑制、神经酰胺积累和复合物III抑制是棕榈酸介导的心脏凋亡的下游事件，并且独立于导致caspase 3样激活的事件发生。
After cardiac ischemia, long-chain fatty acids, such as palmitate, increase in plasma and heart. Palmitate has previously been shown to cause apoptosis in cardiac myocytes. Cultured neonatal rat cardiac myocytes were studied to assess mitochondrial alterations during apoptosis. Phosphatidylserine translocation and caspase 3-like activity confirmed the apoptotic action of palmitate. Cytosolic cytochrome c was detected at 8 h and plateaued at 12 h. The mitochondrial membrane potential (Delta Psi) in tetramethylrhodamine ethyl ester-loaded cardiac myocytes decreased significantly in individual mitochondria by 8 h. This loss was heterogeneous, with a few energized mitochondria per myocyte remaining at 24 h. Total ATP levels remained high at 16 h. The Delta Psi loss was delayed by cyclosporin A, a mitochondrial permeability transition inhibitor. Mitochondrial swelling accompanied changes in Delta Psi. Carnitine palmitoyltransferase I activity fell at 16 h; this decline was accompanied by ceramide increases that paralleled decreased complex III activity. We conclude that carnitine palmitoyltransferase I inhibition, ceramide accumulation, and complex III inhibition are downstream events in cardiac apoptosis mediated by palmitate and occur independent of events leading to caspase 3-like activation.