Hypoxia Inducible-Factor1α Regulates the Metabolic Shift of Pulmonary Hypertensive Endothelial Cells

• Published in: The American journal of pathology Vol. 176; no. 3; pp. 1130 - 1138
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 01.03.2010; American Society for Investigative Pathology
• Subjects: Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Investigative techniques, diagnostic techniques (general aspects); Medical sciences; Pathology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Regular; Hypertension; Anatomic pathology; Endothelial cell; Oxygen; Regulation(control); Lung; Cardiovascular disease; Hypoxia; Metabolism; Respiratory system
• ISSN: 0002-9440; 1525-2191
• DOI: 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-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.