PGC1α-mediated mitofusin-2 deficiency in female rats and humans with pulmonary arterial hypertension

John J. Ryan, Glenn Marsboom, Yong Hu Fang, Peter T. Toth, Erik Morrow, Nancy Luo, Lin Piao, Zhigang Hong, Kyle Ericson, Hannah J. Zhang, Mei Han, Chad R. Haney, Chin Tu Chen, Willard W. Sharp, Stephen L. Archer

Research output: Contribution to journalArticle

106 Scopus citations

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 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 γ coactivator 1-α (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 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 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. Conclusions: 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.

Original languageEnglish (US)
Pages (from-to)865-878
Number of pages14
JournalAmerican journal of respiratory and critical care medicine
Volume187
Issue number8
DOIs
StatePublished - Apr 15 2013
Externally publishedYes

Keywords

  • Female sex
  • Hypoxia-inducible factor-1 α
  • Mitochondrial fission
  • Optic atrophy 1
  • Peroxisome proliferator-activated receptor gamma coactivator-1 α

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Fingerprint Dive into the research topics of 'PGC1α-mediated mitofusin-2 deficiency in female rats and humans with pulmonary arterial hypertension'. Together they form a unique fingerprint.

  • Cite this

    Ryan, J. J., Marsboom, G., Fang, Y. H., Toth, P. T., Morrow, E., Luo, N., Piao, L., Hong, Z., Ericson, K., Zhang, H. J., Han, M., Haney, C. R., Chen, C. T., Sharp, W. W., & Archer, S. L. (2013). PGC1α-mediated mitofusin-2 deficiency in female rats and humans with pulmonary arterial hypertension. American journal of respiratory and critical care medicine, 187(8), 865-878. https://doi.org/10.1164/rccm.201209-1687OC