Hypoxia inducible-factor1α regulates the metabolic shift of pulmonary hypertensive endothelial cells

Iwona Fijalkowska, Weiling Xu, Suzy A A Comhair, Allison J. Janocha, Lori A. Mavrakis, Balaji Krishnamachary, Lijie Zhen, Thianzi Mao, Amy Richter, Serpil C. Erzurum, Rubin M. Tuder

Research output: Contribution to journalArticle

Abstract

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-factor1α (HIF-1α) 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-1α expression and transcriptional activity than controls under normoxia or hypoxia, and pulmonary arteries from affected patients have increased expression of HIF-1α and its target carbonic anhydrase IX. Decreased expression of manganese superoxide dismutase (MnSOD) in IPAH-ECs paralleled increased HIF-1α 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-1α expression in normoxic IPAH-ECs. Finally, mitochondria numbers increased in IPAH-ECs with knockdown of HIF-1α. These findings indicate that alterations of nitric oxide and MnSOD contribute to pathological HIF-1α expression and account for lower numbers of mitochondria in IPAH-ECs.

Original languageEnglish (US)
Pages (from-to)1130-1138
Number of pages9
JournalAmerican Journal of Pathology
Volume176
Issue number3
DOIs
StatePublished - Mar 2010

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Endothelial Cells
Lung
Superoxide Dismutase
Mitochondria
Nitric Oxide
Small Interfering RNA
Hypoxia
Nitric Oxide Donors
Response Elements
Glycolysis
Luciferases
Pulmonary Hypertension
Hypertrophy
Pulmonary Artery
Smooth Muscle Myocytes
Zinc
Copper
Cultured Cells
Apoptosis
Proteins

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Medicine(all)

Cite this

Hypoxia inducible-factor1α regulates the metabolic shift of pulmonary hypertensive endothelial cells. / Fijalkowska, Iwona; Xu, Weiling; Comhair, Suzy A A; Janocha, Allison J.; Mavrakis, Lori A.; Krishnamachary, Balaji; Zhen, Lijie; Mao, Thianzi; Richter, Amy; Erzurum, Serpil C.; Tuder, Rubin M.

In: American Journal of Pathology, Vol. 176, No. 3, 03.2010, p. 1130-1138.

Research output: Contribution to journalArticle

Fijalkowska, I, Xu, W, Comhair, SAA, Janocha, AJ, Mavrakis, LA, Krishnamachary, B, Zhen, L, Mao, T, Richter, A, Erzurum, SC & Tuder, RM 2010, 'Hypoxia inducible-factor1α regulates the metabolic shift of pulmonary hypertensive endothelial cells', American Journal of Pathology, vol. 176, no. 3, pp. 1130-1138. https://doi.org/10.2353/ajpath.2010.090832
Fijalkowska, Iwona ; Xu, Weiling ; Comhair, Suzy A A ; Janocha, Allison J. ; Mavrakis, Lori A. ; Krishnamachary, Balaji ; Zhen, Lijie ; Mao, Thianzi ; Richter, Amy ; Erzurum, Serpil C. ; Tuder, Rubin M. / Hypoxia inducible-factor1α regulates the metabolic shift of pulmonary hypertensive endothelial cells. In: American Journal of Pathology. 2010 ; Vol. 176, No. 3. pp. 1130-1138.
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