The key role of PGC-1α in mitochondrial biogenesis and the proliferation of pulmonary artery vascular smooth muscle cells at an early stage of hypoxic exposure

详细信息    查看全文

• 作者：Jingjing Rao (1)
  Jing Li (1)
  Yun Liu (1)
  Ping Lu (1)
  Xiaojiao Sun (1)
  P. K. Sugumaran (1)
  Daling Zhu (12) dalingz@yahoo.com
• 关键词：PGC ; 1α – Mitochondrial biogenesis – Hypoxia – Pulmonary vascular remodeling – Hypoxic pulmonary hypertension
• 刊名：Molecular and Cellular Biochemistry
• 出版年：2012
• 出版时间：August 2012
• 年：2012
• 卷：367
• 期：1-2
• 页码：9-18
• 全文大小：617.5 KB
• 参考文献：1. Mandegar M, Fung YC, Huang W, Remillard CV, Rubin LJ, Yuan JX (2004) Cellular and molecular mechanisms of pulmonary vascular remodeling: role in the development of pulmonary hypertension. Microvasc Res 68(2):75–103
  2. Humbert M, Sitbon O, Simonneau G (2004) Treatment of pulmonary arterial hypertension. N Engl J Med 351(14):1425–1436
  3. Meyrick B, Reid L (1978) The effect of continued hypoxia on rat pulmonary arterial circulation. An ultrastructural study. Lab Invest 38(2):188–200
  4. Vender RL (1994) Chronic hypoxic pulmonary hypertension. Cell biology to pathophysiology. Chest 106(1):236–243
  5. Stenmark KR, Fagan KA, Frid MG (2006) Hypoxia-induced pulmonary vascular remodeling: cellular and molecular mechanisms. Circ Res 99(7):675–691
  6. Fredenburgh LE, Liang OD, Macias AA, Polte TR, Liu X, Riascos DF, Chung SW, Schissel SL, Ingber DE, Mitsialis SA, Kourembanas S, Perrella MA (2008) Absence of cyclooxygenase-2 exacerbates hypoxia-induced pulmonary hypertension and enhances contractility of vascular smooth muscle cells. Circulation 117(16):2114–2122
  7. Ma C, Li Y, Ma J, Liu Y, Li Q, Niu S, Shen Z, Zhang L, Pan Z, Zhu D (2011) Key role of 15-lipoxygenase/15-hydroxyeicosatetraenoic acid in pulmonary vascular remodeling and vascular angiogenesis associated with hypoxic pulmonary hypertension. Hypertension 58(4):679–688
  8. Wang Z, Tang X, Li Y, Leu C, Guo L, Zheng X, Zhu D (2008) 20-Hydroxyeicosatetraenoic acid inhibits the apoptotic responses in pulmonary artery smooth muscle cells. Eur J Pharmacol 588(1):9–17
  9. Trian T, Benard G, Begueret H, Rossignol R, Girodet PO, Ghosh D, Ousova O, Vernejoux JM, Marthan R, Tunon-de-Lara JM, Berger P (2007) Bronchial smooth muscle remodeling involves calcium-dependent enhanced mitochondrial biogenesis in asthma. J Exp Med 204(13):3173–3181
  10. Isidoro A, Martínez M, Fernández PL, Ortega AD, Santamaría G, Chamorro M, Reed JC, Cuezva JM (2004) Alteration of the bioenergetic phenotype of mitochondria is a hallmark of breast, gastric, lung and oesophageal cancer. Biochem J 378:17–20
  11. Yin W, Signore AP, Iwai M, Cao G, Gao Y, Chen J (2008) Rapidly increased neuronal mitochondrial biogenesis after hypoxic-ischemic brain injury. Stroke 39(11):3057–3063
  12. Rehman J, Archer SL (2010) A proposed mitochondrial-metabolic mechanism for initiation and maintenance of pulmonary arterial hypertension in fawn-hooded rats: the Warburg model of pulmonary arterial hypertension. Adv Exp Med Biol 661:171–185
  13. Archer SL, Marsboom G, Kim GH, Zhang HJ, Toth PT, Svensson EC, Dyck JR, Gomberg-Maitland M, Thébaud B, Husain AN, Cipriani N, Rehman J (2010) Epigenetic attenuation of mitochondrial superoxide dismutase 2 in pulmonary arterial hypertension: a basis for excessive cell proliferation and a new therapeutic target. Circulation 121(24):2661–2671
  14. Archer SL, Gomberg-Maitland M, Maitland ML, Rich S, Garcia JG, Weir EK (2008) Mitochondrial metabolism, redox signaling, and fusion: a mitochondria-ROS-HIF-1alpha-Kv1.5 O2-sensing pathway at the intersection of pulmonary hypertension and cancer. Am J Physiol Heart Circ Physiol 294(2):H570–H578
  15. Fijalkowska I, Xu W, Comhair SA, Janocha AJ, Mavrakis LA, Krishnamachary B, Zhen L, Mao T, Richter A, Erzurum SC, Tuder RM (2010) Hypoxia inducible-factor1alpha regulates the metabolic shift of pulmonary hypertensive endothelial cells. Am J Pathol 176(3):1130–1138
  16. Puigserver P, Wu Z, Park CW, Graves R, Wright M, Spiegelman BM (1998) A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 92(6):829–839
  17. Huss JM, Kopp RP, Kelly DP (2002) Peroxisome proliferator-activated receptor coactivator-1alpha (PGC-1alpha) coactivates the cardiac-enriched nuclear receptors estrogen-related receptor-alpha and -gamma. Identification of novel leucine-rich interaction motif within PGC-1alpha. J Biol Chem 277(43):40265–40274
  18. Michael LF, Wu Z, Cheatham RB, Puigserver P, Adelmant G, Lehman JJ, Kelly DP, Spiegelman BM (2001) Restoration of insulin-sensitive glucose transporter (GLUT4) gene expression in muscle cells by the transcriptional coactivator PGC-1. Proc Natl Acad Sci USA 98(7):3820–3825
  19. J?rgensen SB, Wojtaszewski JF, Viollet B, Andreelli F, Birk JB, Hellsten Y, Schjerling P, Vaulont S, Neufer PD, Richter EA, Pilegaard H (2005) Effects of alpha-AMPK knockout on exercise-induced gene activation in mouse skeletal muscle. FASEB 19(9):1146–1148
  20. Wu Z, Puigserver P, Andersson U, Zhang C, Adelmant G, Mootha V, Troy A, Cinti S, Lowell B, Scarpulla RC, Spiegelman BM (1999) Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 98(1):115–124
  21. Virbasius JV, Scarpulla RC (1994) Activation of the human mitochondrial transcription factor A gene by nuclear respiratory factors: a potential regulatory link between nuclear and mitochondrial gene expression in organelle biogenesis. Proc Natl Acad Sci USA 91(4):1309–1313
  22. Shoag J, Arany Z (2010) Regulation of hypoxia-inducible genes by PGC-1 alpha. Arterioscler Thromb Vasc Biol 30(4):662–666
  23. Arany Z, Foo SY, Ma Y, Ruas JL, Bommi-Reddy A, Girnun G, Cooper M, Laznik D, Chinsomboon J, Rangwala SM, Baek KH, Rosenzweig A, Spiegelman BM (2008) HIF-independent regulation of VEGF and angiogenesis by the transcriptional coactivator PGC-1alpha. Nature 451(7181):1008–1012
  24. Zhu L, Wang Q, Zhang L, Fang Z, Zhao F, Lv Z, Gu Z, Zhang J, Wang J, Zen K, Xiang Y, Wang D, Zhang CY (2010) Hypoxia induces PGC-1α expression and mitochondrial biogenesis in the myocardium of TOF patients. Cell Res 20(6):676–687
  25. Rabinovitch M (2010) PPARgamma and the pathobiology of pulmonary arterial hypertension. Adv Exp Med Biol 661:447–458
  26. Goncharova EA, Ammit AJ, Irani C, Carroll RG, Eszterhas AJ, Panettieri RA, Krymskaya VP (2002) PI3K is required for proliferation and migration of human pulmonary vascular smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 283(2):L354–L363
  27. Gutsaeva DR, Carraway MS, Suliman HB, Demchenko IT, Shitara H, Yonekawa H, Piantadosi CA (2008) Transient hypoxia stimulates mitochondrial biogenesis in brain subcortex by a neuronal nitric oxide synthase-dependent mechanism. J Neurosci 28(9):2015–2024
  28. Lin J, Wu H, Tarr PT, Zhang CY, Wu Z, Boss O, Michael LF, Puigserver P, Isotani E, Olson EN, Lowell BB, Bassel-Duby R, Spiegelman BM (2002) Transcriptional co-activator PGC-1 alpha drives the formation of slow-twitch muscle fibres. Nature 418(6899):797–801
  29. Wright GL, Maroulakou IG, Eldridge J, Liby TL, Sridharan V, Tsichlis PN, Muise-Helmericks RC (2008) VEGF stimulation of mitochondrial biogenesis: requirement of AKT3 kinase. FASEB J 22(9):3264–3275
  30. Han S, Ritzenthaler JD, Sun X, Zheng Y, Roman J (2009) Activation of peroxisome proliferator-activated receptor beta/delta induces lung cancer growth via peroxisome proliferator-activated receptor coactivator gamma-1alpha. Am J Respir Cell Mol Biol 40(3):325–331
• 作者单位：1. Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University (Daqing), Xinyang Road Gaoxin District, Daqing, 163319 Heilongjiang, People’s Republic of China2. Biopharmaceutical Key Laboratory of Heilongjiang Province, Harbin, 150081 People’s Republic of China
• ISSN：1573-4919

文摘

Peroxisome proliferator activated receptor gamma coactivator 1α (PGC-1α) induced by hypoxia regulates mitochondrial biogenesis and oxidative stress. However, the potential role of PGC-1α in hypoxia-promoted proliferation of pulmonary arterial vascular smooth muscle cells (PASMCs) is completely unknown. In this study, we found that hypoxia significantly induced the expression of PGC-1α in cultured PASMCs and activated mitochondrial biogenesis through upregulation of nuclear respiratory factor-1 and mitochondria transcription factor A in a time-dependent manner. Knockdown of PGC-1α by siRNA abrogated hypoxia-induced PASMCs proliferation via the downregulation of PCNA, cyclinA, and cyclinE. Furthermore, we observed that PI3K/Akt signaling pathway was involved in hypoxia induced PGC-1α expression and PASMCs proliferation. Taken together, these datas reveal PGC-1α as the key regulator to mediate mitochondrial biogenesis and the proliferation of PASMCs at an early stage of hypoxic exposure. This process might bring to light a potential adaptive mechanism for PASMCs to minimize hypoxic damage and our novel findings provide new insight into the development of hypoxic pulmonary hypertension.