PGC1α-mediated Mitofusin-2 Deficiency in Female Rats and Humans with Pulmonary Arterial Hypertension

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 pr...

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Published in:American journal of respiratory and critical care medicine 2013-04, Vol.187 (8), p.865-878
Main Authors: RYAN, John J, MARSBOOM, Glenn, MEI HAN, HANEY, Chad R, CHEN, Chin-Tu, SHARP, Willard W, ARCHER, Stephen L, FANG, Yong-Hu, TOTH, Peter T, MORROW, Erik, LUO, Nancy, LIN PIAO, ZHIGANG HONG, ERICSON, Kyle, ZHANG, Hannah J
Format: Article
Language:English
Subjects:
Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy
Animals
Apoptosis - physiology
Biological and medical sciences
Cell Proliferation - drug effects
Disease Models, Animal
Diseases of visual field, optic nerve, optic chiasma and optic tracts
Disorders of higher nervous function. Focal brain diseases. Central vestibular syndrome and deafness. Brain stem syndromes
Exercise Tolerance - drug effects
Familial Primary Pulmonary Hypertension
Female
GTP Phosphohydrolases - deficiency
Heat-Shock Proteins - deficiency
Humans
Hypertension, Pulmonary - genetics
Hypertension, Pulmonary - pathology
Hypertension, Pulmonary - physiopathology
Intensive care medicine
Lung - cytology
Lung - pathology
Medical sciences
Membrane Proteins - administration & dosage
Membrane Proteins - deficiency
Mitochondrial Dynamics - genetics
Mitochondrial Dynamics - physiology
Mitochondrial Proteins - administration & dosage
Mitochondrial Proteins - deficiency
Myocytes, Smooth Muscle - pathology
Myocytes, Smooth Muscle - physiology
Nervous system (semeiology, syndromes)
Neurology
Ophthalmology
Optic Atrophy, Autosomal Dominant - genetics
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
Pneumology
Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases
Rats
Rats, Sprague-Dawley
Transcription Factors - deficiency
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Summary: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. 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 γ coactivator 1-α (PGC1α), was assessed. MFN2 therapy was tested in PAH PASMC and in models of PAH. 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. 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 ± 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. Decreased expression of MFN2 and PGC1α contribute to mitochondrial fragmentation and a proliferation-apoptosis imbalance in human and experimental PAH. Augmenting MFN2 has therapeutic benefit in human and experimental PAH.
ISSN:1073-449X
1535-4970
DOI:10.1164/rccm.201209-1687OC