Potential Roles of Metals in the Pathogenesis of Pulmonary and Systemic Hypertension

Abstract

Pulmonary and systemic hypertension (PH, SH) are characterized by vasoconstriction and vascular remodeling resulting in increased vascular resistance and pulmonary/aortic artery pressures. The chronic stress leads to inflammation, oxidative stress, and infiltration by immune cells. Roles of metals in these diseases, particularly PH are largely unknown. This review first discusses the pathophysiology of PH including vascular oxidative stress, inflammation, and remodeling in PH; mitochondrial dysfunction and metabolic changes in PH; ion channel and its alterations in the pathogenesis of PH as well as PH-associated right ventricular (RV) remodeling and dysfunctions. This review then summarizes metal general features and essentiality for the cardiovascular system and effects of metals on systemic blood pressure. Lastly, this review explores non-essential and essential metals and potential roles of their dyshomeostasis in PH and RV dysfunction. Although it remains early to conclude the role of metals in the pathogenesis of PH, emerging direct and indirect evidence implicates the possible contributions of metal-mediated toxicities in the development of PH. Future research should focus on comprehensive clinical metallomics study in PH patients; mechanistic evaluations to elucidate roles of various metals in PH animal models; and novel therapy clinical trials targeting metals. These important discoveries will significantly advance our understandings of this rare yet fatal disease, PH.

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

Figure 1

The are multiple hypothesized factors that contribute to the decreased lumen diameter characteristic of PAH, many centered around the development of a hypoxic state and increased concentration of heavy metals. (1) Healthy pulmonary arteries are highly compliant to meet the homeostatic demands of the heart (RV=right ventricle, LV=left ventricle) and peripheral circulation. (2) In states of low oxygen availability, HIF-alpha is stabilized and thus activated. HIF-alpha stabilization upregulates PDK1/2 expression in apoptotic-resistant pulmonary endothelial and smooth muscle cells, thus decreasing oxidative phosphorylation and promoting the production of ROS. A shift towards increased ROS production in mitochondria consequently decreases NO synthesis, thus allowing for unregulated vasoconstriction of pulmonary arteries. (3) Idiopathic PAH presents with increased lymphocyte infiltration of endothelial cells, resulting in activation and an increased in inflammatory cytokine release (i.e., IL-1, IL-6). IL-1 upregulates FGF-2, which promotes smooth muscle cell proliferation and thus decreased lumen size. (4) Decreased pulmonary artery compliance over time leads to cardiac right ventricular remodeling, a complication frequently seen in PAH patients.

Figure 2

In response to the decreased oxygen availability associated with not only PAH but also heavy metal exposure, HIF-alpha is stabilized and thus activated. Stabilized HIF-alpha promotes translocation of hexokinase II into the mitochondria, thus inhibiting Kv1.5 activity and hyperpolarizing the mitochondrial membrane. Stabilized HIF-alpha also induces upregulation of pyruvate dehydrogenase kinases 1 and 2 (PDK 1/2), resulting in decreased pyruvate dehydrogenase (PDH) activity. PDH is an essential upstream enzyme in mitochondrial oxidative phosphorylation, and inhibition of this enzyme decreases oxygen reduction and consequently increases superoxide ion (O₂^-) production, i.e.: reactive oxygen species (ROS). O₂^- is then either spontaneously interacts with nitric oxide (NO, reactive nitrogen species, RNS) to form more reactive RNS, peroxynitrite (ONOO) or is converted to another ROS called hydrogen peroxide (H₂O₂) via superoxide dismutase (SOD), which is then broken down into water and oxygen by the enzyme catalase. Metallothioneins (MTs) are cysteine-rich heavy metal and ROS/RNS scavengers. They have been shown to be beneficial in the treatment of PAH by binding to and reducing the activity of ROS/RNS, like ONOO, and thus limiting the oxidative damage of arterial lipids, DNA, and proteins.

Figure 3

Zinc regulation by its transporters (ZIPs and ZnTs) and metallothionein (MT).