Contribution of fatty acid oxidation to the pathogenesis of pulmonary hypertension.
Michael H LeeLinda SandersRahul KumarDaniel Hernandez-SaavedraXin YunJoshay A FordMario J PerezClaudia MickaelAneta GandjevaDaniel E KoyanagiJulie W HarralDavid C IrwinBiruk KassaRobert H EckelLarissa A ShimodaBrian B GrahamRubin M TuderPublished in: American journal of physiology. Lung cellular and molecular physiology (2022)
Dysregulated metabolism characterizes both animal and human forms of pulmonary hypertension (PH). Enzymes involved in fatty acid metabolism have previously not been assessed in human pulmonary arteries affected by pulmonary arterial hypertension (PAH), and how inhibition of fatty acid oxidation (FAO) may attenuate PH remains unclear. Fatty acid metabolism gene transcription was quantified in laser-dissected pulmonary arteries from 10 explanted lungs with advanced PAH (5 idiopathic, 5 associated with systemic sclerosis), and 5 donors without lung diseases. Effects of oxfenicine, a FAO inhibitor, on female Sugen 5416-chronic hypoxia (SuHx) rats were studied in vivo using right heart catheterization, and ex vivo using perfused lungs and pulmonary artery ring segments. The impact of pharmacologic (oxfenicine) and genetic (carnitine palmitoyltransferase 1a heterozygosity) FAO suppression was additionally probed in mouse models of Schistosoma and hypoxia-induced PH. Potential mechanisms underlying FAO-induced PH pathogenesis were examined by quantifying ATP and mitochondrial mass in oxfenicine-treated SuHx pulmonary arterial cells, and by assessing pulmonary arterial macrophage infiltration with immunohistochemistry. We found upregulated pulmonary arterial transcription of 26 and 13 FAO genes in idiopathic and systemic sclerosis-associated PAH, respectively. In addition to promoting de-remodeling of pulmonary arteries in SuHx rats, oxfenicine attenuated endothelin-1-induced vasoconstriction. FAO inhibition also conferred modest benefit in the two mouse models of PH. Oxfenicine increased mitochondrial mass in cultured rat pulmonary arterial cells, and decreased the density of perivascular macrophage infiltration in pulmonary arteries of treated SuHx rats. In summary, FAO inhibition attenuated experimental PH, and may be beneficial in human PAH.
Keyphrases
- pulmonary hypertension
- pulmonary artery
- pulmonary arterial hypertension
- systemic sclerosis
- fatty acid
- endothelial cells
- interstitial lung disease
- high glucose
- induced apoptosis
- oxidative stress
- adipose tissue
- coronary artery
- hydrogen peroxide
- copy number
- climate change
- pluripotent stem cells
- cell death
- high resolution
- rheumatoid arthritis
- cell cycle arrest
- gene expression
- signaling pathway
- high speed
- pi k akt
- stress induced
- genome wide analysis