Reprogramming of Iron and Oxygen Metabolism Across the Spectrum of Primary Aldosteronism

Primary aldosteronism (PA) causes oxidative stress, myocardial injury, and increases hemoglobin, whereas aldosterone antagonists mitigate myocardial injury and lower hemoglobin. Whether these phenomena involve altered iron and oxygen metabolism is unknown. To investigate this, we leveraged human physiology studies that characterized the spectrum of PA, from subclinical to clinically overt renin-independent aldosteronism. The plasma proteome was measured to conduct aldosterone dose-response analyses to identify iron and oxygen metabolism related pathways. CYBRD1, a mediator of iron reduction and absorption, was the most abundant protein in people with overt PA, and Reactome enrichment identified 16 iron and heme-related pathways involving erythrocyte oxygen handling, heme biosynthesis, and mitochondrial respiratory electron transport. Across the continuum of PA, there were progressive decreases in mitochondrial electron transport proteins, and increases in hemoglobin subunits, heme-related proteins, and erythrocyte oxygen-handling enzymes. These proteomic changes were validated by demonstrating aldosterone dose-dependent increases in circulating hemoglobin in this cohort and an independent population-based cohort. Collectively, PA is characterized by progressive decreases in mitochondrial oxidative phosphorylation, and increases in iron absorption, heme synthesis, and oxygen-delivery, possibly reflecting a compensatory response to cellular pseudohypoxia. These findings provide a mechanistic basis for aldosterone-mediated myocardial injury and the benefits of aldosterone-directed therapy.