The Iron Paradigm of Pulmonary Arterial Hypertension

Iron is a metal not only important in maintaining the structural integrity of the Earth’s core but also the normal physiological function of metazoans. In fact, the requirement of iron as a cofactor for iron–sulfur and iron-dependent proteins, many of which are involved in a host of metabolic and regulatory pathways, helped form the foundation for the iron–sulfur world theory on the origin of life by the German chemist Gunter Wachtershauser.1 It is therefore not surprising that a shift in the delicate balance of iron levels is implicated in a variety of pathological conditions that seem to have an underlying metabolic abnormality. For example, iron overload can increase the risk of metabolic syndrome,2 whereas iron deficiency is associated with cancer.3Article, see p 1680 A newly emerging metabolic disease is pulmonary arterial hypertension (PAH), a complex vascular remodeling disease resulting in pulmonary artery (PA) occlusion with an accompanying right ventricular (RV) hypertrophy and failure.4,5 PAH PA vascular cells, including endothelial cells, smooth muscle cells, and fibroblasts, seem to have a metabolic switch from mitochondrial-derived glucose oxidation to cytoplasmic-derived glycolysis,6–8 similar to cancer.9 The complexity of this disease is due, in part, to a diverse range of activated signaling pathways in the proliferative and apoptosis-resistant PA smooth muscle cells (PASMCs). These pathways range from activation of proproliferative transcription factors, such as hypoxia-inducible factor 1α, signal transducer and activator of transcription 3 and nuclear factor of activated T cells to induced epigenetic modifications, including microRNA aberrant expression,10 methylation resulting in decreased expression of mitochondrial enzymes, such as manganese superoxide dismutase11 or single-nucleotide polymorphisms to sirtuin-3.12 Although a primary mitochondrial suppression in PASMCs has provided strong evidence for how many of these seemingly unrelated pathways may converge into 1 central …