Abstract 19935: Imbalance in Mitochondrial Fusion and Fission in Pulmonary Artery Smooth Muscle Cells (PASMC) from Patients with Pulmonary Arterial Hypertension (PAH)
Introduction: An imbalance in the PASMC proliferation/apoptosis ratio (favoring proliferation) is involved in the pathogenesis of PAH. Mitochondria are dynamic organelles that continuously undergo fission and fusion. Although the purposes of fusion and fission remain undefined, they are essential for cell division, protection of mitochondrial DNA and likely are relevant to mitochondrial metabolism and redox signaling. We previously observed that the mitochondrial network in PASMC from PAH patients and rodents were fragmented and that this was associated with a glycolytic metabolic shift and a reduced redox environment. Three mitochondrial guanosine triphosphatases mediate fusion: mitofusin-1 and -2 and OPA1. Two mitochondrial proteins, Fis1 and (dynamin related protein 1, Drp1), are involved mitochondrial fission.
Hypothesis: We assed the hypothesis that there is an imbalance in the expression of the proteins that mediate fusion (notably mitofusin 1 and 2) and fission (Drp-1) favoring Drp-1 and fission.
Methods and Results: Cultures of PASMC from normal subjects and humans with WHO category 1 pulmonary hypertension (PAH) were obtained from University of Chicago and University of Minnesota (<passage 8). Expression of the mRNA for genes relevant to fission and fusion was measured using qRT-PCR using B2M as a reporter. We also assessed compartment specific redox state using the redox sensitive green fluorescent protein report system (roGFP). The expression of genes responsible for mitochondrial fusion (mitofusin 1 and 2) is decreased in resistance PASMC from PAH patient compared to that of norm subjects. Conversely, the expression of the mitochondrial fission gene (Drp1) is increased in PAH compared to norm control. One of the associated consequences of this disturbance in network formation was a change in cytosolic redox state. The cytosolic compartment was more reduced and less responsive to changes in PO2 (acute hypoxia) in PAH vs control PASMC.
Conclusions: An imbalance in the expression of Drp-1 relative to the mitofusins may account for the observed fragmentation of the mitochondrial network in PAH PASMC and may, through effects of cytosolic redox state, contribute to the imbalance proliferation/apoptosis that characterizes PAH.
- © 2010 by American Heart Association, Inc.