Nogo-B Receptor Directs Mitochondria-Associated Membranes to Regulate Vascular Smooth Muscle Cell Proliferation

Abstract

Mitochondria-associated membranes (MAM) are a well-recognized contact link between the mitochondria and endoplasmic reticulum that affects mitochondrial biology and vascular smooth muscle cells (VSMCs) proliferation via the regulation of mitochondrial Ca2+(Ca2+m) influx. Nogo-B receptor (NgBR) plays a vital role in proliferation, epithelial-mesenchymal transition, and chemoresistance of some tumors. Recent studies have revealed that downregulation of NgBR, which stimulates the proliferation of VSMCs, but the underlying mechanism remains unclear. Here, we investigated the role of NgBR in MAM and VSMC proliferation. We analyzed the expression of NgBR in pulmonary arteries using a rat model of hypoxic pulmonary hypertension (HPH), in which rats were subjected to normoxic recovery after hypoxia. VSMCs exposed to hypoxia and renormoxia were used to assess the alterations in NgBR expression in vitro. The effect of NgBR downregulation and overexpression on VSMC proliferation was explored. The results revealed that NgBR expression was negatively related with VSMCs proliferation. Then, MAM formation and the phosphorylation of inositol 1,4,5-trisphosphate receptor type 3 (IP3R3) was detected. We found that knockdown of NgBR resulted in MAM disruption and augmented the phosphorylation of IP3R3 through pAkt, accompanied by mitochondrial dysfunction including decreased Ca2+m, respiration and mitochondrial superoxide, increased mitochondrial membrane potential and HIF-1α nuclear localization, which were determined by confocal microscopy and Seahorse XF-96 analyzer. By contrast, NgBR overexpression attenuated IP3R3 phosphorylation and HIF-1α nuclear localization under hypoxia. These results reveal that dysregulation of NgBR promotes VSMC proliferation via MAM disruption and increased IP3R3 phosphorylation, which contribute to the decrease of Ca2+m and mitochondrial impairment.

Nogo-B promotes epithelial-mesenchymal transition in lung fibrosis via PERK branch of the endoplasmic reticulum stress pathway

“…Because Nogo-B is widely expressed in ER, it functions as a crucial protein for maintaining the ER-mitochondria unit (22) and plays an important role in protein folding, ER homeostasis, and lipid biosynthesis (23). It was recently reported Nogo-B can regulate the distance between ER and mitochondria when stress exists (24). Moreover, recent research demonstrated that upregulating Nogo-B expression helps to inhibit the proliferation of pulmonary artery smooth muscle cells, oxidative stress and ER stress (25).…”

Nogo-B receptor is required for stabilizing TGF-β type Ireceptor and promotes the TGF-β1-induced epithelial-to-mesenchymal transition of non-small cell lung cancer

“…Nogo-B receptor (NgBR) is a receptor that specifically binds to Nogo-B [18]. It is a single transmembrane protein that functions mainly in the remodeling and the formation of blood vessels [19][20][21]. Studies in recent years have shown that NgBR plays an essential role in tumor progression [22,23].…”

Molecular Dysfunctions of Mitochondria‐Associated Endoplasmic Reticulum Contacts in Atherosclerosis

“…VSMC apoptosis accelerates atherogenesis and the progression of advanced lesions, leading to atherosclerotic plaque vulnerability and medial degeneration, suggesting MAM may be a new target to modulate VSMC fate and favor atherosclerotic plaque stability [23]. In addition, knocking out NgBR can cause MAM destruction and increase the phosphorylation of IPR3 through pAkt, is accompanied by mitochondrial dysfunction, including decreased Ca 2+ respiration and mitochondrial superoxide, and increased mitochondrial membrane potential and HIF-1α nuclear localization, indicating that the dysregulation of NgBR promotes VSMC proliferation through the destruction of MAM and the increase of IPR3 phosphorylation, thereby contributing to reduce Ca 2+ and mitochondrial damage [76].…”