The effect of mitoTEMPO on the development of hypoxia‐induced pulmonary hypertension in male mice

TL;DR

This study finds that mitoTEMPO, an antioxidant targeting mitochondria, does not prevent hypoxia-induced pulmonary hypertension in mice.

Contribution

The study provides new evidence that mitoTEMPO lacks therapeutic benefit for hypoxia-induced PH.

Findings

MitoTEMPO treatment did not reduce chronic hypoxia-induced pulmonary hypertension in mice.

MitoTEMPO did not inhibit hypoxia-induced proliferation of pulmonary arterial smooth muscle cells.

MitoTEMPO did not alter HIF-1α stabilization or downstream gene expression under hypoxic or normoxic conditions.

Abstract

Mitochondrial reactive oxygen species (mtROS) have been implicated in the development of chronic hypoxia‐induced pulmonary hypertension (PH), potentially through hypoxia‐inducible factor‐1α (HIF‐1α) stabilization. However, the role of mtROS in HIF‐1α stabilization, PH development, and the therapeutic potential of antioxidant treatment remains controversial. Mice were exposed to hypoxia (10% O2) for 4 weeks to induce PH and treated with mitochondria‐targeted antioxidant mitoTEMPO or its carrier control, triphenylphosphonium (TPP+). Cell proliferation was evaluated in mouse pulmonary arterial smooth muscle cells (PASMCs) by BrdU incorporation. HIF‐1α stabilization and downstream target expression were investigated in mouse lung carcinoma epithelial (CMT167) cells and isolated mouse and human PASMCs under different hypoxic conditions. In vivo mitoTEMPO treatment did not affect chronic hypoxia‐induced PH compared to TPP+. In vitro, mitoTEMPO treatment did not inhibit hypoxia‐induced mouse PASMCs proliferation but enhanced proliferation under normoxic conditions. In vitro exposure of CMT167 cells and mouse or human PASMCs to mitoTEMPO or TPP+ did not alter HIF‐1α protein levels or expression of its downstream targets lactate dehydrogenase A (Ldha) and pyruvate dehydrogenase kinase 1 (Pdk1) under normoxic (21% O2) or hypoxic (1% or 10% O2) conditions after 24 h. These findings do not support a therapeutic benefit of mitoTEMPO in hypoxia‐induced PH.

MitoTEMPO targets mitochondrial superoxide (O2•−) but showed no protective effect on chronic hypoxia–induced pulmonary hypertension. Pulmonary artery remodeling and right ventricular remodeling developed despite treatment.

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