Amphetamines promote mitochondrial dysfunction and DNA damage in pulmonary hypertension

Area of Science:

• Biomedical Science
• Cardiovascular Research
• Toxicology

Background:

• Amphetamine (AMPH) and methamphetamine (METH) abuse are linked to oxidative damage and pulmonary arterial hypertension (PAH).
• Patients with AMPH-associated PAH exhibit DNA damage in pulmonary artery endothelial cells (PAECs).

Purpose of the Study:

• To investigate the hypothesis that AMPH induces DNA damage and vascular pathology by interfering with adaptive responses to oxidative stress.
• To elucidate the molecular mechanisms by which AMPH exacerbates DNA damage in PAECs under hypoxic conditions.

Main Methods:

• Exposure of normoxic and hypoxic PAECs to AMPH.
• Assessment of DNA damage using γH2AX foci and comet assays.
• Analysis of molecular signaling pathways including protein phosphatase 2A, Akt, sirtuin 1, and HIF1α.
• Evaluation of mitochondrial function and reactive oxygen species (ROS) production.
• In vivo studies using mice treated with METH followed by hypoxia.

Main Results:

• AMPH alone did not induce DNA damage in normoxic PAECs but significantly amplified damage in hypoxic PAECs.
• AMPH activated protein phosphatase 2A, inhibited Akt, increased sirtuin 1, and led to HIF1α degradation.
• This resulted in reduced pyruvate dehydrogenase kinase 1, impaired cytochrome c oxidase 4 isoform switch, enhanced mitochondrial oxidative phosphorylation, and increased mitochondrial ROS.
• Caspase-3 activation and DNA damage were induced under these conditions.
• METH-treated mice exposed to hypoxia showed suppressed HIF1α and increased pulmonary artery DNA damage, correlating with vascular remodeling.

Conclusions:

• AMPH and METH subvert adaptive responses to oxidative stress, leading to DNA damage and vascular pathology.
• The mechanism involves the disruption of the Akt/sirtuin 1/HIF1α pathway, impairing cellular defense against hypoxia-induced oxidative stress.
• Chronic stimulant abuse can induce DNA damage and contribute to the pathogenesis of vascular diseases like PAH.