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
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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ABSTRACT: RATIONALE: Pulmonary arterial hypertension (PAH) is a lethal, female-predominant, vascular disease. Pathologic changes in PA smooth muscle cells (PASMC) include excessive proliferation, apoptosis-resistance and mitochondrial fragmentation. Activation of dynamin-related protein increases mitotic fission and promotes proliferation/apoptosis imbalance. The contribution of decreased fusion and reduced mitofusin-2 (MFN2) expression to PAH is unknown. OBJECTIVES: We hypothesize that decreased MFN2 expression promotes mitochondrial fragmentation, increases proliferation and impairs apoptosis. The role of MFN2's transcriptional co-activator, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α, was assessed. MFN2 therapy was tested in PAH PASMC and in models of PAH. METHODS: Fusion and fission mediators were measured in lungs and PASMC from PAH patients and female rats with monocrotaline- or chronic hypoxia+Sugen-5416 (CH+SU)-PAH. The effects of adenoviral-mitofusin-2 (Ad-MFN2) overexpression were measured in vitro and in vivo. RESULTS: In normal PASMC, siMFN2 reduced expression of MFN2 and PGC1α; conversely, siPGC1α reduced PGC1α and MFN2 expression. Both interventions caused mitochondrial fragmentation. siMFN2 increased proliferation. In rodent and human PAH PASMC, MFN2 and PGC1α were decreased and mitochondria were fragmented. Ad-MFN2 increased fusion, reduced proliferation and increased apoptosis in human PAH and CH+SU. In CH+SU, Ad-MFN2 improved walking distance (381±35 vs 245±39m, p<0.05), decreased pulmonary vascular resistance (0.18±0.02 vs 0.38±0.14 mmHg/ml/min, p<0.05) and decreased PA medial thickness (14.5±0.8 vs 19.0±1.7%, p<0.05). Lung vascularity was increased by MFN2. CONCLUSIONS: MFN2 and PGC1α expression are decreased in human and experimental PAH contributing to mitochondrial fragmentation and a proliferation/apoptosis imbalance in PAH. Augmenting MFN2 has therapeutic benefit in human and experimental PAH.
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ABSTRACT: Cardiovascular disease (CVD) risk factors, such as diabetes, hypertension, dyslipidemia, obesity and physical inactivity, are all correlated with impaired endothelial Nitric Oxide Synthase (eNOS) function and decreased nitric oxide (NO) production. NO-mediated regulation of mitochondrial biogenesis has been established in many tissues, yet the role of eNOS in vascular mitochondrial biogenesis and dynamics is unclear. We hypothesized that genetic eNOS deletion and 3-day NOS inhibition in rodents would result in impaired mitochondrial biogenesis and defunct fission/fusion and autophagy profiles within the aorta. We observed a significant, eNOS expression-dependent decrease in mitochondrial electron transport chain (ETC) protein subunits from complexes I, II, III, and V in eNOS heterozygotes and eNOS null mice compared to age-matched controls. In response to NOS inhibition with L(g)-Nitro-Arginine Methyl Ester (L-NAME) treatment in Sprague Dawley rats, significant decreases were observed in ETC protein subunits from complexes I, III, and IV as well as VDAC1. Decreased protein content of upstream regulators of mitochondrial biogenesis, CREB and PGC1-α, were observed in response to 3-day L-NAME treatment. Both genetic eNOS deletion and NOS inhibition resulted in decreased MnSOD protein. L-NAME treatment resulted in significant changes to mitochondrial dynamics protein profiles with decreased fusion, increased fission, and minimally perturbed autophagy. In addition, L-NAME treatment blocked mitochondrial adaptation to an exercise intervention in the aorta. These results suggest that eNOS/NO play a role in basal and adaptive mitochondrial biogenesis in the vasculature and regulation of mitochondrial turnover.
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