The zinc transporter ZIP12 regulates monocrotaline-induced proliferation and migration of pulmonary arterial smooth muscle cells via the AKT/ERK signaling pathways

Abstract

Background The zinc transporter ZIP12 is a membrane-spanning protein that transports zinc ions into the cytoplasm from the extracellular space. Recent studies demonstrated that upregulation of ZIP12 is involved in elevation of cytosolic free zinc and excessive proliferation of pulmonary arterial smooth muscle cells (PASMCs) induced by hypoxia. However, the expression of ZIP12 and its role in pulmonary arterial hypertension (PAH) induced by monocrotaline (MCT) in rats have not been evaluated previously. The aim of this study was to investigate the effect of ZIP12 on the proliferation and migration of PASMCs and its underlying mechanisms in MCT-induced PAH. Methods A PAH rat model was generated by intraperitoneal injection of 20 mg/kg MCT twice at one-week intervals. PASMCs were isolated from the pulmonary arteries of rats with MCT-induced PAH or control rats. The expression of ZIP12 and related molecules was detected in the lung tissues and cells. A ZIP12 knockdown lentivirus and an overexpressing lentivirus were constructed and transfected into PASMCs derived from PAH and control rats, respectively. EdU assays, wound healing assays and Western blotting were carried out to explore the function of ZIP12 in PASMCs. Results Increased ZIP12 expression was observed in PASMCs derived from MCT-induced PAH rats. The proliferation and migration of PASMCs from PAH rats were significantly increased compared with those from control rats. These results were corroborated by Western blot analysis of PCNA and cyclin D1. All these effects were significantly reversed by silencing ZIP12. Comparatively, ZIP12 overexpression resulted in the opposite effects as shown in PASMCs from control rats. Furthermore, selective inhibition of AKT phosphorylation by LY294002 abolished the effect of ZIP12 overexpression on enhancing cell proliferation and migration and partially suppressed the increase in ERK1/2 phosphorylation induced by ZIP12 overexpression. However, inhibition of ERK activity by U0126 resulted in partial reversal of this effect and did not influence an increase in AKT phosphorylation induced by ZIP12 overexpression. Conclusions ZIP12 is involved in MCT-induced pulmonary vascular remodeling and enhances the proliferation and migration of PASMCs. The mechanism of these effects was partially mediated by enhancing the AKT/ERK signaling pathways.

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

“…Inhibition of ZIP12 expression significantly or partially prevented hypoxia-induced PAH, RV hypertrophy and vascular remodeling than wild type rats, suggesting the essential role of ZIP12 expression in the pathogenesis of PH. This important finding was further supported by the subsequent studies with different conditions 157 , 158 .…”

Loss of Slc39a12 in hippocampal neurons is responsible for anxiety-like behavior caused by temporomandibular joint osteoarthritis

“…Members of the solute carrier 39 gene family encoding zinc transport proteins contribute to critical mechanisms, by which zinc homeostasis can be maintained across a wide range of species. Their main function is to promote the uptake of the extracellular environment and transport Zn 2+ into cells [ 40 ]. A previous study showed that oxidative stress reduced the expression of zinc transporters in hepatocytes.…”

SOCS5, targeted by miR-155-5p, plays a negative regulatory role in pulmonary hypertension through inhibiting JAK2/STAT3 signaling pathway

“…Pulmonary vascular remodeling mainly occurs in pulmonary artery smooth muscle cells (PASMCs), endothelial cells and fibroblasts in the vascular wall. Excessive PASMCs proliferation and migration tends to cause pulmonary vascular remodeling and trigger PH [ 30 ]. In this study, we found that SOCS5 expression was low in PASMCs, and overexpression of SOCS5 inhibited the abnormal proliferation and migration of HPASMCs under hypoxia in vitro, while knockdown of SOCS5 promoted it.…”