title: Amphetamines promote mitochondrial dysfunction and DNA damage in pulmonary hypertension.
abstract: Amphetamine (AMPH) or methamphetamine (METH) abuse can cause oxidative damage and is a risk factor for diseases including pulmonary arterial hypertension (PAH). Pulmonary artery endothelial cells (PAECs) from AMPH-associated-PAH patients show DNA damage as judged by γH2AX foci and DNA comet tails. We therefore hypothesized that AMPH induces DNA damage and vascular pathology by interfering with normal adaptation to an environmental perturbation causing oxidative stress. Consistent with this, we found that AMPH alone does not cause DNA damage in normoxic PAECs, but greatly amplifies DNA damage in hypoxic PAECs. The mechanism involves AMPH activation of protein phosphatase 2A, which potentiates inhibition of Akt. This increases sirtuin 1, causing deacetylation and degradation of HIF1α, thereby impairing its transcriptional activity, resulting in a reduction in pyruvate dehydrogenase kinase 1 and impaired cytochromecoxidase 4 isoform switch. Mitochondrial oxidative phosphorylation is inappropriately enhanced and, as a result of impaired electron transport and mitochondrial ROS increase, caspase-3 is activated and DNA damage is induced. In mice given binge doses of METH followed by hypoxia, HIF1α is suppressed and pulmonary artery DNA damage foci are associated with worse pulmonary vascular remodeling. Thus, chronic AMPH/METH can induce DNA damage associated with vascular disease by subverting the adaptive responses to oxidative stress.
authors.forename: Pin-I
authors.initials: PI
authors.lastname: Chen
authors.forename: Aiqin
authors.initials: A
authors.lastname: Cao
authors.forename: Kazuya
authors.initials: K
authors.lastname: Miyagawa
authors.forename: Nancy F
authors.initials: NF
authors.lastname: Tojais
authors.forename: Jan K
authors.initials: JK
authors.lastname: Hennigs
authors.forename: Caiyun G
authors.initials: CG
authors.lastname: Li
authors.forename: Nathaly M
authors.initials: NM
authors.lastname: Sweeney
authors.forename: Audrey S
authors.initials: AS
authors.lastname: Inglis
authors.forename: Lingli
authors.initials: L
authors.lastname: Wang
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.forename: Matthew
authors.initials: M
authors.lastname: Ye
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Feldman
authors.forename: Marlene
authors.initials: M
authors.lastname: Rabinovitch
mesh_terms: D000328:Adult; D019969:Amphetamine-Related Disorders / Q000235:genetics* / Q000378:metabolism; D000662:Amphetamines / Q000494:pharmacology*; D000818:Animals; D053148:Caspase 3 / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects*; D004579:Electron Transport / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics* / Q000378:metabolism; D000860:Hypoxia / Q000235:genetics* / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D051379:Mice; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D010085:Oxidative Phosphorylation; D054648:Protein Phosphatase 2 / Q000187:drug effects / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D017382:Reactive Oxygen Species / Q000378:metabolism; D056564:Sirtuin 1 / Q000187:drug effects / Q000378:metabolism; D066253:Vascular Remodeling / Q000187:drug effects / Q000235:genetics
chemical_list: D000662:Amphetamines; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D017382:Reactive Oxygen Species; D008694:Methamphetamine; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D054648:Protein Phosphatase 2; C505409:Casp3 protein, mouse; D053148:Caspase 3; D056564:Sirtuin 1
keywords: Cell Biology; Vascular Biology