Abstract
Pulmonary vascular remodeling and increased arterial wall stiffness are two major causes for the elevated pulmonary vascular resistance and pulmonary arterial pressure in patients and animals with pulmonary hypertension. Cellular copper (Cu) plays an important role in angiogenesis and extracellular matrix remodeling; increased Cu in vascular smooth muscle cells has been demonstrated to be associated with atherosclerosis and hypertension in animal experiments. In this study, we show that the Cu-uptake transporter 1, CTR1, and the Cu-efflux pump, ATP7A, were both upregulated in the lung tissues and pulmonary arteries of mice with hypoxia-induced pulmonary hypertension. Hypoxia also significantly increased expression and activity of lysyl oxidase (LOX), a Cu-dependent enzyme that causes crosslinks of collagen and elastin in the extracellular matrix. In vitro experiments show that exposure to hypoxia or treatment with cobalt (CoCl2) also increased protein expression of CTR1, ATP7A, and LOX in pulmonary arterial smooth muscle cells (PASMC). In PASMC exposed to hypoxia or treated with CoCl2, we also confirmed that the Cu transport is increased using 64Cu uptake assays. Furthermore, hypoxia increased both cell migration and proliferation in a Cu-dependent manner. Downregulation of hypoxia-inducible factor 1α (HIF-1α) with siRNA significantly attenuated hypoxia-mediated upregulation of CTR1 mRNA. In summary, the data from this study indicate that increased Cu transportation due to upregulated CTR1 and ATP7A in pulmonary arteries and PASMC contributes to the development of hypoxia-induced pulmonary hypertension. The increased Cu uptake and elevated ATP7A also facilitate the increase in LOX activity and thus the increase in crosslink of extracellular matrix, and eventually leading to the increase in pulmonary arterial stiffness.
Highlights
Pulmonary arterial hypertension (PAH) is a severe, progressive disease of the pulmonary circulation manifested by increased pulmonary arterial pressure (PAP) and elevated pulmonary vascular resistance (PVR) that can lead to right ventricular failure and death [1,2]
Upregulated mRNA and protein expression of Cu transporters in lung and pulmonary artery tissues isolated from mice with hypoxia-induced pulmonary hypertension (HPH) To examine whether Cu transportation is involved in the development of HPH, we first measured and compared mRNA and protein levels of the Cu transporters (CTR1 and ATP7A), Cu chaperones (ATOX1 and Cu chaperone for SOD1 (CCS)) and Cu-dependent enzymes (LOX) in lung tissues from normoxic and hypoxic mice
We identified a novel mechanism in which chronic hypoxia caused increased Cu transport and lysyl oxidase (LOX) activity that promoted the development of pulmonary hypertension in a murine model
Summary
Pulmonary arterial hypertension (PAH) is a severe, progressive disease of the pulmonary circulation manifested by increased pulmonary arterial pressure (PAP) and elevated pulmonary vascular resistance (PVR) that can lead to right ventricular failure and death [1,2]. The pathogenic mechanism responsible for the elevated of PAP and PVR results from sustained pulmonary vasoconstriction and progressive pulmonary vascular remodeling [3] The latter involves pulmonary arterial medial hypertrophy due to a combination of excessive proliferation (‘‘muscularization’’), decreased apoptosis of smooth muscle cells, adventitial thickening from excessive deposition of collagen and elastin [4,5,6,7,8], endothelial dysfunction leading to the plexiform arteriopathy [9], and luminal obliteration. The propensity of Cu to donate and accept electrons makes it potentially toxic through generation of hydroxyl free radicals via Fenton chemistry [13] For these reasons, it is important that the intracellular Cu concentration is tightly regulated [14]
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