Abstract
Iron–sulfur (Fe-S) clusters are essential for mitochondrial metabolism, but their regulation in pulmonary hypertension (PH) remains enigmatic. We demonstrate that alterations of the miR-210-ISCU1/2 axis cause Fe-S deficiencies in vivo and promote PH. In pulmonary vascular cells and particularly endothelium, hypoxic induction of miR-210 and repression of the miR-210 targets ISCU1/2 down-regulated Fe-S levels. In mouse and human vascular and endothelial tissue affected by PH, miR-210 was elevated accompanied by decreased ISCU1/2 and Fe-S integrity. In mice, miR-210 repressed ISCU1/2 and promoted PH. Mice deficient in miR-210, via genetic/pharmacologic means or via an endothelial-specific manner, displayed increased ISCU1/2 and were resistant to Fe-S-dependent pathophenotypes and PH. Similar to hypoxia or miR-210 overexpression, ISCU1/2 knockdown also promoted PH. Finally, cardiopulmonary exercise testing of a woman with homozygous ISCU mutations revealed exercise-induced pulmonary vascular dysfunction. Thus, driven by acquired (hypoxia) or genetic causes, the miR-210-ISCU1/2 regulatory axis is a pathogenic lynchpin causing Fe-S deficiency and PH. These findings carry broad translational implications for defining the metabolic origins of PH and potentially other metabolic diseases sharing similar underpinnings.
Highlights
Iron–sulfur (Fe-S) clusters ([4Fe-4S] and [2Fe-2S]) are critical bioinorganic prosthetic groups that are essential for electron transport and consequent metabolic processes (Beinert et al, 1997)
Based on our prior studies of the regulation of miR-210 in pulmonary arterial endothelial cells (PAECs) (Chan et al, 2009) and the up-regulation of both HIF-1a and HIF-2a in vascular endothelial cells in hypoxia-relevant Pulmonary hypertension (PH) in mice (Supplementary Fig S1), we hypothesized that the miR-210-ISCU1/2 axis is active in various forms of PH stemming from hypoxia-dependent or HIF-dependent activity
By RT–PCR, we found that miR-210 was induced in the lungs of mice deficient in the von Hippel–Lindau gene (VHLÀ/À), a genetic model of PH driven by constitutive HIF-a activation (Fig 1A, Supplementary Fig S2A). miR-210 was up-regulated in lungs of mice suffering from PH stemming from chronic hypoxia (10% O2) (Supplementary Fig S2B) and in mouse lungs with more severe PH (Supplementary Fig S2A) stemming from chronic hypoxia accompanied by serial administration of the VEGF-receptor antagonist
Summary
Iron–sulfur (Fe-S) clusters ([4Fe-4S] and [2Fe-2S]) are critical bioinorganic prosthetic groups that are essential for electron transport and consequent metabolic processes (Beinert et al, 1997). Stemming from the relatively rare occurrence of these genetic mutations and technical obstacles to measuring these prosthetic groups in mammals, the regulation and actions of Fe-S clusters in the wide spectrum of human metabolic disease have been poorly investigated. PH is defined by increased pulmonary arterial pressure and lung vasculopathy, triggered by varied and often disparate stimuli (Schermuly et al, 2011) Among these triggers, hypoxia and the actions of its master transcription factors of hypoxia, HIF-1a and HIF-2a, are well-recognized insults in multiple PH subtypes, including pulmonary arterial hypertension (PAH, WHO Group 1) (Bonnet et al, 2006; Fijalkowska et al, 2010; Farha et al, 2011; Marsboom et al, 2012) as well as PH associated with hypoxic lung diseases (WHO Group 3) (as reviewed by Tuder et al, 2013). Some factors have been identified to modulate metabolic processes in the diseased pulmonary vasculature, but the entire complement of regulators remains undefined
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