A hypothesis: Potential contributions of metals to the pathogenesis of pulmonary artery hypertension

Abstract

Pulmonary artery hypertension (PAH) is characterized by vasoconstriction and vascular remodeling resulting in both increased pulmonary vascular resistance (PVR) and pulmonary artery pressure (PAP). The chronic and high-pressure stress experienced by endothelial cells can give rise to inflammation, oxidative stress, and infiltration by immune cells. However, there is no clearly defined mechanism for PAH and available treatment options only provide limited symptomatic relief. Due to the far-reaching effects of metal exposures, the interaction between metals and the pulmonary vasculature is of particular interest. This review will briefly introduce the pathophysiology of PAH and then focus on the potential roles of metals, including essential and non-essential metals in the pathogenic process in the pulmonary arteries and right heart, which may be linked to PAH. Based on available data from human studies of occupational or environmental metal exposure, including lead, antimony, iron, and copper, the hypothesis of metals contributing to the pathogenesis of PAH is proposed as potential risk factors and underlying mechanisms for PAH. We propose that metals may initiate or exacerbate the pathogenesis of PAH, by providing potential mechanism by which metals interact with hypoxia-inducible factor and tumor suppressor p53 to modulate their downstream cellular proliferation pathways. These need further investigation. Additionally, we present future research directions on roles of metals in PAH.

Keywords: Heavy metals; Mineral homeostasis; Non-essential metals; Pulmonary hypertension; Pulmonary hypoxia; Right ventricle dysfunction; Trace elements.

Figure 1.. The proposed hypothesis.

We hypothesize that exposure to metals, particularly non-essential metal, that either (1) directly damages endothelial cells of pulmonary arteries via Fenton reaction to generate free radicals, or (2) interacts with essential metals via competing for their transporters to cause intracellular essential metal dyshomeostasis that can lead essential metals-dependent enzyme, transcriptional factors, signaling pathway kinase dysfunction, and mitochondrial dysfunction or damage, all which can cause mitochondria-mediated metabolic changes, oxidative stress, chronic inflammation. Therefore, specific chelation of nonessential metal or specific supplementation of certain deficient essential metals may prevent these metal effects on PAH pathogenesis. In addition, non-essential metals or/and essential metals dyshomeostasis may accelerate PAH pathogenesis from other nonmetal PAH risk factors. PAH=Pulmonary artery hypertension.

Figure 2.. Metal potential effects on HIF-1α- and P53-mediated cell proliferation.

A: Illustration of oxygen-dependent regulation of HIF-1α signaling: under normoxic conditions, HIF-1α is hydroxylated by PHD2 and the hydroxylated HIF-1α binds von Hippel–Lindau (VHL) and subsequently undergoes HIF-1α poly-ubiquitylation and degradation while under hypoxic conditions, hydroxylation and acetylation are inhibited, HIF-1α accumulates and forms dimers with HIF-1β, and then translocate into nuclear to form complex with p300/CBP to transcriptionally upregulate their downstream genes, including VEGF to stimulate cell proliferation. In addition, increased ROS generation under hypoxic conditions results in disulfde bond-mediated PHD2 homo-dimer formation via thiol groups of cysteine residues in the catalytic site, thus decreasing enzyme activity. Meanwhile ROS also oxidizes PHD2 Fe2 to Fe3, leading to the reduction of PHD2 activity. HIF-1α-mediated pathways are stimulated by copper, zinc, cobalt (Co) and nonessential metals (As, Ni, Cr6 and Cd). B: Wild-type Zn-bound p53 transcriptionally upregulated P21 and E2F1 to ensue proliferate cell arrest at G1/S phase with inhibition of VEGF expression, meanwhile Zn-bound p53 can also downregulate HIF-1/2α, COX2 and bFGF to prevent their stimulating effect on VEGF or cell proliferation. Since Zn bound p53 can be replaced under certain conditions, p53 protein conformation is changed with loss of its normal function.