Hypoxia Inducible-Factor1α Regulates the Metabolic Shift of Pulmonary Hypertensive Endothelial Cells
Hypoxia Inducible-Factor1α Regulates the Metabolic Shift of Pulmonary Hypertensive Endothelial Cells
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DOI：
10.2353/ajpath.2010.090832
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发表时间：
2010-03-01
影响因子：
6
通讯作者：
Tuder, Rubin M.
中科院分区：
文献类型：
--
作者：
Fijalkowska, Iwona;Xu, Weiling;Tuder, Rubin M.
严重的肺动脉高压是不可逆转的，通常是致命的。本病血管内皮细胞(ECs)异常增殖、抗凋亡和平滑肌细胞肥大与线粒体减少和糖酵解优先产生能量有关。我们推测，肺动脉高压内皮细胞的这种代谢变化是由于低水平的一氧化氮和低的超氧化物歧化酶活性引起的低氧诱导因子1α(HIF-1α)的表达。我们发现，培养的特发性肺动脉高压患者的内皮细胞在常氧或低氧条件下比对照组有更高的HIF-1a表达和转录活性，来自受影响患者的肺动脉内皮细胞HIF-1α及其靶向碳酸酐酶IX的表达增加。常氧内皮细胞的HIF-1α水平和小干扰(SI)RNA的表达水平增加，而铜锌超氧化物歧化酶的表达水平和低氧反应元件(HRE)诱导的荧光素酶活性则无明显变化，同时IPAH-ECs中MnSOD的表达减少。MnSODsiRNA还可减少IPAH-ECs上清液中一氧化氮的产生。相反，低水平的一氧化氮供体减少了正常缺氧的IPAH-ECs中HIF-1α的表达。最后，随着HIF-1α基因的下调，IPAH-ECs中线粒体数量增加。这些结果表明，一氧化氮和MnSOD的改变参与了病理性HIF-1α的表达，并解释了IPAH-ECs中线粒体数量减少的原因。(Am J Pathol 2010,176：1130-1136DOI：10.2353/ajpath.2010.090832)
Severe pulmonary hypertension is irreversible and often fatal. Abnormal proliferation and resistance to apoptosis of endothelial cells (ECs) and hypertrophy of smooth muscle cells in this disease are linked to decreased mitochondria and preferential energy generation by glycolysis. We hypothesized this metabolic shift of pulmonary hypertensive ECs is due to greater hypoxia inducible-factor1 alpha (HIF-1 alpha) expression caused by low levels of nitric oxide combined with low superoxide dismutase activity. We show that cultured ECs from patients with idiopathic pulmonary arterial hypertension (IPAH-ECs) have greater HIF-1a expression and transcriptional activity than controls under normoxia or hypoxia, and pulmonary arteries from affected patients have increased expression of HIF-1 alpha and its target carbonic anhydrase IX. Decreased expression of manganese superoxide dismutase (MnSOD) in IPAH-ECs paralleled increased HIF-1 alpha levels and small interfering (SI) RNA knockdown of MnSOD, but not of the copper-zinc SOD, increased HIF-1 protein expression and hypoxia response element (HRE)-driven luciferase activity in normoxic ECs. MnSOD siRNA also reduced nitric oxide production in supernatants of IPAH-ECs. Conversely, low levels of a nitric oxide donor reduced HIF-1 alpha expression in normoxic IPAH-ECs. Finally, mitochondria numbers increased in IPAH-ECs with knockdown of HIF-1 alpha. These findings indicate that alterations of nitric oxide and MnSOD contribute to pathological HIF-1 alpha expression and account for lower numbers of mitochondria in IPAH-ECs. (Am J Pathol 2010,176:1130-1136 DOI: 10.2353/ajpath.2010.090832)