Amphetamines promote mitochondrial dysfunction and DNA damage in pulmonary hypertension
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Amphetamines promote mitochondrial dysfunction and DNA damage in pulmonary hypertension. / Chen, Pin-I; Cao, Aiqin; Miyagawa, Kazuya; Tojais, Nancy F; Hennigs, Jan K; Li, Caiyun G; Sweeney, Nathaly M; Inglis, Audrey S; Wang, Lingli; Li, Dan; Ye, Matthew; Feldman, Brian J; Rabinovitch, Marlene.
in: JCI INSIGHT, Jahrgang 2, Nr. 2, 26.01.2017, S. e90427.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Amphetamines promote mitochondrial dysfunction and DNA damage in pulmonary hypertension
AU - Chen, Pin-I
AU - Cao, Aiqin
AU - Miyagawa, Kazuya
AU - Tojais, Nancy F
AU - Hennigs, Jan K
AU - Li, Caiyun G
AU - Sweeney, Nathaly M
AU - Inglis, Audrey S
AU - Wang, Lingli
AU - Li, Dan
AU - Ye, Matthew
AU - Feldman, Brian J
AU - Rabinovitch, Marlene
PY - 2017/1/26
Y1 - 2017/1/26
N2 - 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.
AB - 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.
U2 - 10.1172/jci.insight.90427
DO - 10.1172/jci.insight.90427
M3 - SCORING: Journal article
C2 - 28138562
VL - 2
SP - e90427
JO - JCI INSIGHT
JF - JCI INSIGHT
SN - 2379-3708
IS - 2
ER -