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 cytochrome c oxidase 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.
Keywords:
Cell Biology; Vascular Biology.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adult
-
Amphetamine-Related Disorders / genetics*
-
Amphetamine-Related Disorders / metabolism
-
Amphetamines / pharmacology*
-
Animals
-
Caspase 3 / drug effects
-
Caspase 3 / metabolism
-
DNA Damage / drug effects*
-
Electron Transport / drug effects
-
Endothelial Cells / drug effects*
-
Endothelial Cells / metabolism
-
Female
-
Humans
-
Hypertension, Pulmonary / genetics*
-
Hypertension, Pulmonary / metabolism
-
Hypoxia / genetics*
-
Hypoxia / metabolism
-
Hypoxia-Inducible Factor 1, alpha Subunit / drug effects
-
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
-
In Vitro Techniques
-
Male
-
Methamphetamine / pharmacology*
-
Mice
-
Middle Aged
-
Mitochondria / drug effects*
-
Mitochondria / metabolism
-
Oxidative Phosphorylation
-
Protein Phosphatase 2 / drug effects
-
Protein Phosphatase 2 / metabolism
-
Protein Serine-Threonine Kinases / drug effects
-
Protein Serine-Threonine Kinases / metabolism
-
Proto-Oncogene Proteins c-akt / drug effects
-
Proto-Oncogene Proteins c-akt / metabolism
-
Pulmonary Artery / drug effects
-
Pulmonary Artery / metabolism
-
Pyruvate Dehydrogenase Acetyl-Transferring Kinase
-
Reactive Oxygen Species / metabolism
-
Sirtuin 1 / drug effects
-
Sirtuin 1 / metabolism
-
Vascular Remodeling / drug effects
-
Vascular Remodeling / genetics
Substances
-
Amphetamines
-
Hif1a protein, mouse
-
Hypoxia-Inducible Factor 1, alpha Subunit
-
Pyruvate Dehydrogenase Acetyl-Transferring Kinase
-
Reactive Oxygen Species
-
Methamphetamine
-
Protein Serine-Threonine Kinases
-
Proto-Oncogene Proteins c-akt
-
Protein Phosphatase 2
-
Casp3 protein, mouse
-
Caspase 3
-
Sirtuin 1