Author + information
- John Ryan,
- Glenn Marsboom,
- Yong Hu Fang,
- Peter Toth,
- Erik Morrow,
- Nancy Luo,
- Zhigang Hong,
- Kyle Ericson,
- Hannah Zhang,
- Chad Haney,
- Chin-Tu Chen,
- Willard Sharp and
- Stephen Archer
Excess smooth muscle cell (PASMC) proliferation contributes to vascular obstruction in pulmonary arterial hypertension (PAH). We recently described a role for impaired mitochondrial fusion in this proliferative diasthesis due to decreased expression of mitofusin-2 (MFN2). We hypothesize that decreased expression of proliferator-activated receptor gamma coactivator gene (PGC1α) reduces MFN2 expression, resulting in impaired mitochondrial fusion and increased PASMC proliferation.
Expression of PGC1α was performed in lungs and PASMC from PAH patients and chronic hypoxia+Sugen-5416 (CH+SU) rats. Small inhibitory RNA (siRNA) was used to downregulate PGC1α or MFN2.
PAH-PASMC were hyperproliferative with fragmented mitochondria and decreased expression of PGC1α and MFN2. SiPGC1α reduced MFN2 expression in PASMC. SiMFN2 reduced PGC1α expression (Fig 1A). SiPGC1α and siMFN2 caused mitochondrial fragmentation (Fig 1B). SiMFN2 increased PASMC proliferation. Augmenting MFN2 using a serotype-5, adenoviral vector (Ad-MFN2) increased expression of MFN2 and PGC1α in human and CH+SU PASMC (Fig 1C), increased fusion and decreased PASMC proliferation.
PGC1α regulates MFN2 expression in PASMC. A reciprocal relationship exists between MFN2 and PGC1α. Decreased PGC1α and MFN2 in PAH and CH+SU PASMC contributes to mitochondrial fragmentation and PASMC hyperproliferation. Augmenting MFN2 or PGC1α may have potential as antiproliferative therapies in PAH.
Poster Sessions, Expo North
Monday, March 11, 2013, 9:45 a.m.-10:30 a.m.
Session Title: Pulmonary Hypertension: Pre-Clinical, Clinical, Biomarkers
Abstract Category: 27. Pulmonary Hypertension
Presentation Number: 1294-143
- 2013 American College of Cardiology Foundation