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PGC1alpha-mediated mitofusin-2 deficiency in female rats and humans with pulmonary arterial hypertension Ryan JJ; Marsboom G; Fang YH; Toth PT; Morrow E; Luo N; Piao L; Hong Z; Ericson K; Zhang HJ; Han M; Haney CR; Chen CT; Sharp WW; Archer SLAm J Respir Crit Care Med 2013[Apr]; 187 (8): 865-78RATIONALE: 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 this 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 coactivator, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1alpha), 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 patients with PAH 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. MEASUREMENTS AND MAIN RESULTS: In normal PASMC, siMFN2 reduced expression of MFN2 and PGC1alpha; conversely, siPGC1alpha reduced PGC1alpha and MFN2 expression. Both interventions caused mitochondrial fragmentation. siMFN2 increased proliferation. In rodent and human PAH PASMC, MFN2 and PGC1alpha 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 +/- 39 m; P < 0.05); decreased pulmonary vascular resistance (0.18 +/- 0.02 vs. 0.38 +/- 0.14 mm Hg/ml/min; P < 0.05); and decreased PA medial thickness (14.5 +/- 0.8 vs. 19 +/- 1.7%; P < 0.05). Lung vascularity was increased by MFN2. CONCLUSIONS: Decreased expression of MFN2 and PGC1alpha contribute to mitochondrial fragmentation and a proliferation-apoptosis imbalance in human and experimental PAH. Augmenting MFN2 has therapeutic benefit in human and experimental PAH.|Animals[MESH]|Apoptosis/physiology[MESH]|Cell Proliferation/drug effects[MESH]|Disease Models, Animal[MESH]|Exercise Tolerance/drug effects[MESH]|Familial Primary Pulmonary Hypertension[MESH]|Female[MESH]|GTP Phosphohydrolases/*deficiency[MESH]|Heat-Shock Proteins/*deficiency[MESH]|Humans[MESH]|Hypertension, Pulmonary/genetics/pathology/*physiopathology[MESH]|Lung/cytology/pathology[MESH]|Membrane Proteins/administration & dosage/deficiency[MESH]|Mitochondrial Dynamics/genetics/*physiology[MESH]|Mitochondrial Proteins/administration & dosage/*deficiency[MESH]|Myocytes, Smooth Muscle/pathology/physiology[MESH]|Optic Atrophy, Autosomal Dominant/genetics[MESH]|Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha[MESH]|Rats[MESH]|Rats, Sprague-Dawley[MESH]|Transcription Factors/*deficiency[MESH] |
