Abstract 12102: Right Ventricular Failure in Pulmonary Hypertension is Associated with Abnormal Mitochondrial Biogenesis
Right ventricular failure (RVF) complicates severe pulmonary arterial hypertension (PAH). While molecular mechanisms of pulmonary vascular remodeling in PAH have been investigated, experimental data elucidating the mechanisms of chronic RVF remain incomplete. We aimed to describe mitochondrial biology abnormalities present in our animal model of RVF. PAH was induced in rats by an SC injection of a VEGFR-blocker followed by 4 wks of hypoxia (SuHx). RVF was confirmed by echocardiogram. Mitochondrial structure was evaluated by electron microscopy (EM). Gene and protein expression were evaluated by RT-PCR and western blot. RVF tissue from SuHx rats demonstrated a 60% reduction in the gene expression of PGC-1α, a key regulator of mitochondrial biogenesis (p=0.001). PGC-1α directly co-activates NRF-2 to induce mitochondrial biogenesis. As shown for PGC-1α, NRF-2 mRNA levels were downregulated in RVF. Moreover, five genes encoding critical enzymes required for mitochondrial DNA replication/maintenance (Fig. A) were also downregulated. Paradoxically, RVF tissue exhibited a 2-fold increase in the amount of mitochondrial DNA (mtDNA) and EM demonstrated an increased number of mitochondria with abnormal shape, size and distribution (Fig B-C). Three mtDNA-encoded proteins ND4L, CytB and MTCO1, were significantly downregulated in RVF tissue. mtDNA is highly susceptible to oxidative stress, therefore we evaluated the expression of the 8-oxoguanine DNA glycosylase (OGG1), an enzyme required for mtDNA repair. RVF tissue exhibited decreased levels of OGG1 protein in comparison to controls. To confirm whether mtDNA in RVF was indeed functionally abnormal, we sequenced the entire mtDNA looking for mutations.
Conclusions: RVF demonstrates an increased number of abnormal, residual mitochondria likely harboring abnormal mtDNA, whereas mitochondrial biogenesis is impaired. Accumulation of dysfunctional mitochondria could contribute to the development of RVF in PAH
- © 2011 by American Heart Association, Inc.