Effect of Mitofusin 2 on smooth muscle cells proliferation in hypoxic pulmonary hypertension

Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang, PR China.
Microvascular Research (Impact Factor: 2.13). 07/2012; 84(3). DOI: 10.1016/j.mvr.2012.06.010
Source: PubMed


Mitofusin 2 (Mfn2) is an important mitochondrial protein in maintaining mitochondrial network and bioenergetics. Recently, Mfn2 has been reported to have a potential role in regulating cell proliferation, apoptosis, and differentiation in many cell types. In this study, we performed immunohistochemistry, pulmonary artery smooth muscle cells (PASMCs) DNA analysis, proliferating cell nuclear antigen expression and cell cycle analysis to determine the role of Mfn2 in hypoxia-induced pulmonary vascular remodeling. Our results showed that hypoxia promoted the proliferation of pulmonary artery smooth muscle cells, including regulating more cells at G(2)/M+S phase, increasing proliferating cell nuclear antigen and Cyclin A expression, whereas all these effects of hypoxia were suppressed after the cells were treated with siRNA against Mfn2. Our results also proved that PI3K/Akt signaling pathway was involved in Mfn2-induced smooth muscle cell proliferation. Thus, these results indicate that Mfn2 mediates PASMC proliferation in hypoxic pulmonary hypertension via the PI3K/Akt signaling pathway.

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    ABSTRACT: Genetic studies in familial pulmonary arterial hypertension (FPAH) have revealed heterozygous germline mutations in the bone morphogenetic protein type II receptor (BMPR-II), a receptor for the transforming growth factor (TGF)-beta/bone morphogenetic protein (BMP) superfamily. PAH is characterized by intense remodeling of small pulmonary arteries by myofibroblast and smooth muscle proliferation. BMPR-II mutation in pulmonary artery smooth muscle cells contributes to abnormal growth responses to BMPs and TGF-beta. Reduced expression or function of BMPR-II signaling leads to exaggerated TGF-beta signaling and altered cellular responses to TGF-beta. The likely mechanism involves an interaction between BMP and TGF-beta-regulated Smad pathways. In endothelial cells, BMPR-II mutation increases the susceptibility of cells to apoptosis. The combination of increased endothelial apoptosis and failure of growth suppression in pulmonary artery smooth muscle cells provides important clues to the cellular pathogenesis of PAH. The reciprocal regulation of TGF-beta and BMP signaling in models of tissue repair may provide new approaches to our understanding of lung disease.
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