The Crossroads of Iron with Hypoxia and Cellular Metabolism. Implications in the Pathobiology of Pulmonary Hypertension

Abstract

The pathologic hallmark of pulmonary arterial hypertension (PAH) is pulmonary vascular remodeling, characterized by endothelial cell proliferation, smooth muscle hypertrophy, and perivascular inflammation, ultimately contributing to increased pulmonary arterial pressures. Several recent studies have observed that iron deficiency in patients with various forms of PAH is associated with worsened clinical outcome. Iron plays a key role in many cellular processes regulating the response to hypoxia, oxidative stress, cellular proliferation, and cell metabolism. Given the potential importance of iron supplementation in patients with the disease and the broad cellular functions of iron, we review its role in processes that pertain to PAH. Clinical RelevanceThis manuscript details the complexities of how disordered iron metabolism, with iron deficiency being one of the most common nutritional deficits in the world, may act to alter the pathobiology of pulmonary vascular disease and other hypoxia-related illnesses.

Non‐anaemic iron deficiency impairs response to pulmonary rehabilitation in COPD

“…1 Moreover, it has been demonstrated that endurance training increases cytochrome c concentration in the presence of sufficient cellular iron resources, 31,32 providing a rationale for the higher training effects seen in NIS patients both in terms of ΔV'O2peak and percentage of responders to endurance training than NAID patients, as shown in this study.…”

“…1 Moreover, iron is an essential nutrient that plays a central role in cellular bioenergetics. Aerobic metabolism is critically dependent on iron-containing proteins, such as haemoglobin (Hb) and cytochrome c. The latter facilitates cellular oxygen utilization in the mitochondrial respiratory chain.…”

“…13 The alterations of the oxygen pathway can limit aerobic capacity and compromise health status in COPD. 14 Given the potential importance of iron supplementation in patients and its broad cellular functions, 1 NAID is a factor that should be taken into account in the analysis of aerobic capacity in COPD patients. Moreover, since pulmonary rehabilitation (PR) is a core component of COPD management, 15 the assessment of NAID impact on exercise training response might be relevant to optimize PR outcomes in COPD patients.…”

Iron is associated with the development of hypoxia-induced pulmonary vascular remodeling in mice

“…We provided that iron restriction led a modest attenuation of hypoxiainduced pulmonary vascular remodeling in mice. Iron is reported to be associated with the pathogenesis of several cardiovascular diseases, including PH [9]. Moreover, disrupted pulmonary iron homeostasis has been reported in several chronic lung diseases [10].…”

Relationship of Iron Deficiency and Serum Ferritin Levels With Pulmonary Hypertension: The Jackson Heart Study

“…Iron plays a critical role in oxygen transport and iron depletion affects regulation of hypoxia-inducible factors [3]. In a preclinical study, a reduction in iron and ferritin levels resulted in marked pulmonary vascular remodeling that was reversed by iron supplementation [4].…”