title: BMPR2 preserves mitochondrial function and DNA during reoxygenation to promote endothelial cell survival and reverse pulmonary hypertension.
abstract: Mitochondrial dysfunction, inflammation, and mutant bone morphogenetic protein receptor 2 (BMPR2) are associated with pulmonary arterial hypertension (PAH), an incurable disease characterized by pulmonary arterial (PA) endothelial cell (EC) apoptosis, decreased microvessels, and occlusive vascular remodeling. We hypothesized that reduced BMPR2 induces PAEC mitochondrial dysfunction, promoting a pro-inflammatory or pro-apoptotic state. Mice with EC deletion of BMPR2 develop hypoxia-induced pulmonary hypertension that, in contrast to non-transgenic littermates, does not reverse upon reoxygenation and is associated with reduced PA microvessels and lung EC p53, PGC1α and TFAM, regulators of mitochondrial biogenesis, and mitochondrial DNA. Decreasing PAEC BMPR2 by siRNA during reoxygenation represses p53, PGC1α, NRF2, TFAM, mitochondrial membrane potential, and ATP and induces mitochondrial DNA deletion and apoptosis. Reducing PAEC BMPR2 in normoxia increases p53, PGC1α, TFAM, mitochondrial membrane potential, ATP production, and glycolysis, and induces mitochondrial fission and a pro-inflammatory state. These features are recapitulated in PAECs from PAH patients with mutant BMPR2.
authors: Department of Pediatrics and Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; The Vera Moulton Wall Center for Pulmonary Vascular Disease, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors: Isabel
authors: I
authors: Diebold
authors: Department of Pediatrics and Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; The Vera Moulton Wall Center for Pulmonary Vascular Disease, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors: Jan K
authors: JK
authors: Hennigs
authors: Department of Pediatrics and Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; The Vera Moulton Wall Center for Pulmonary Vascular Disease, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors: Kazuya
authors: K
authors: Miyagawa
authors: Department of Pediatrics and Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; The Vera Moulton Wall Center for Pulmonary Vascular Disease, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors: Caiyun G
authors: CG
authors: Li
authors: Department of Pediatrics and Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; The Vera Moulton Wall Center for Pulmonary Vascular Disease, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors: Nils P
authors: NP
authors: Nickel
authors: Department of Pediatrics and Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; The Vera Moulton Wall Center for Pulmonary Vascular Disease, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors: Mark
authors: M
authors: Kaschwich
authors: Department of Pediatrics and Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; The Vera Moulton Wall Center for Pulmonary Vascular Disease, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors: Aiqin
authors: A
authors: Cao
authors: Department of Pediatrics and Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; The Vera Moulton Wall Center for Pulmonary Vascular Disease, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors: Lingli
authors: L
authors: Wang
authors: Department of Pediatrics and Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors: Sushma
authors: S
authors: Reddy
authors: Department of Pediatrics and Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; The Vera Moulton Wall Center for Pulmonary Vascular Disease, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors: Pin-I
authors: PI
authors: Chen
authors: Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors: Kiichi
authors: K
authors: Nakahira
authors: Department of Pediatrics and Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; The Vera Moulton Wall Center for Pulmonary Vascular Disease, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors: Miguel A Alejandre
authors: MA
authors: Alcazar
authors: Department of Pediatrics and Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; The Vera Moulton Wall Center for Pulmonary Vascular Disease, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors: Rachel K
authors: RK
authors: Hopper
authors: Department of Pediatrics and Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors: Lijuan
authors: L
authors: Ji
authors: Department of Pediatrics and Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors: Brian J
authors: BJ
authors: Feldman
authors: Department of Pediatrics and Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; The Vera Moulton Wall Center for Pulmonary Vascular Disease, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: marlener@stanford.edu.
authors: Marlene
authors: M
authors: Rabinovitch
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000378:metabolism; D002470:Cell Survival / Q000502:physiology*; D004247:DNA / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D042783:Endothelial Cells / Q000502:physiology*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D057809:HEK293 Cells; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000503:physiopathology; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D008954:Models, Biological; D016133:Polymerase Chain Reaction; D011651:Pulmonary Artery / Q000166:cytology / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics; D012038:Regeneration / Q000502:physiology*
chemical_list: D017931:DNA Primers; D034741:RNA, Small Interfering; D004247:DNA; C498219:Bmpr2 protein, mouse; D052006:Bone Morphogenetic Protein Receptors, Type II