Mitochondrial fission induced by platelet-derived growth factor regulates vascular smooth muscle cell bioenergetics and cell proliferation.
Mitochondrial fission induced by platelet-derived growth factor regulates vascular smooth muscle cell bioenergetics and cell proliferation.
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DOI：
10.1016/j.redox.2013.10.011
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发表时间：
2013
期刊：
影响因子：
11.4
通讯作者：
Hill BG
中科院分区：
文献类型：
--
作者：
Salabei JK;Hill BG
血管平滑肌细胞（VSMCs）在动脉疾病中表现出高度增殖和合成的表型。由于这种表型变化可能与细胞的能量状态相结合，我们假设细胞代谢的变化调节了VSMC的可塑性。将VSMCs暴露于血小板衍生生长因子- bb （PDGF）中，检测线粒体形态、增殖、收缩蛋白表达和线粒体代谢的变化。VSMCs暴露于PDGF导致线粒体断裂和mitofusin 2丰度降低50%。合成VSMCs显示葡萄糖氧化降低20%，同时脂肪酸氧化增加。通透化细胞的线粒体功能检测结果显示，PDGF处理对线粒体呼吸链容量和偶联的影响不大。用线粒体分裂抑制剂mdivi -1治疗VSMCs，可抑制pdgf诱导的线粒体断裂50%，并消除细胞增殖的增加；然而，它不能阻止pdgf介导的自噬激活和收缩蛋白的去除。此外，Mdivi-1治疗逆转了与合成表型相关的脂肪酸和葡萄糖氧化的变化。这些结果表明，线粒体形态和生物能量学的变化是合成VSMC表型超增殖特征的基础，但不影响收缩蛋白的降解。线粒体断裂发生在过渡到合成表型可能是一个治疗靶点的增殖性血管疾病。PDGF促进血管平滑肌细胞线粒体断裂。PDGF增加了对脂肪酸的代谢依赖。线粒体分裂调节增殖和生物能量学。pdgf诱导的生物能量和自噬反应调节去分化。
Vascular smooth muscle cells (VSMCs) develop a highly proliferative and synthetic phenotype in arterial diseases. Because such phenotypic changes are likely integrated with the energetic state of the cell, we hypothesized that changes in cellular metabolism regulate VSMC plasticity. VSMCs were exposed to platelet-derived growth factor-BB (PDGF) and changes in mitochondrial morphology, proliferation, contractile protein expression, and mitochondrial metabolism were examined. Exposure of VSMCs to PDGF resulted in mitochondrial fragmentation and a 50% decrease in the abundance of mitofusin 2. Synthetic VSMCs demonstrated a 20% decrease in glucose oxidation, which was accompanied by an increase in fatty acid oxidation. Results of mitochondrial function assays in permeabilized cells showed few changes due to PDGF treatment in mitochondrial respiratory chain capacity and coupling. Treatment of VSMCs with Mdivi-1—an inhibitor of mitochondrial fission—inhibited PDGF-induced mitochondrial fragmentation by 50% and abolished increases in cell proliferation; however, it failed to prevent PDGF-mediated activation of autophagy and removal of contractile proteins. In addition, treatment with Mdivi-1 reversed changes in fatty acid and glucose oxidation associated with the synthetic phenotype. These results suggest that changes in mitochondrial morphology and bioenergetics underlie the hyperproliferative features of the synthetic VSMC phenotype, but do not affect the degradation of contractile proteins. Mitochondrial fragmentation occurring during the transition to the synthetic phenotype could be a therapeutic target for hyperproliferative vascular disorders. PDGF promotes mitochondrial fragmentation in vascular smooth muscle cells. PDGF increases metabolic reliance on fatty acids. Mitochondrial fragmentation regulates proliferation and bioenergetics. PDGF-induced bioenergetic and autophagic responses regulate de-differentiation.
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