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Metabolic gene remodeling and mitochondrial dysfunction in failing right ventricular hypertrophy secondary to pulmonary arterial hypertension.

Authors: Gomez-Arroyo, J  Mizuno, S  Szczepanek, K  Van Tassell, B  Natarajan, R  Dos Remedios, CG  Drake, JI  Farkas, L  Kraskauskas, D  Wijesinghe, DS  Chalfant, CE  Bigbee, J  Abbate, A  Lesnefsky, EJ  Bogaard, HJ  Voelkel, NF 
Citation: Gomez-Arroyo J, etal., Circ Heart Fail. 2013 Jan;6(1):136-44. doi: 10.1161/CIRCHEARTFAILURE.111.966127. Epub 2012 Nov 14.
Pubmed: (View Article at PubMed) PMID:23152488
DOI: Full-text: DOI:10.1161/CIRCHEARTFAILURE.111.966127

BACKGROUND: Right ventricular (RV) dysfunction (RVD) is the most frequent cause of death in patients with pulmonary arterial hypertension. Although abnormal energy substrate use has been implicated in the development of chronic left heart failure, data describing such metabolic remodeling in RVD remain incomplete. Thus, we sought to characterize metabolic gene expression changes and mitochondrial dysfunction in functional and dysfunctional RV hypertrophy. METHODS AND RESULTS: Two different rat models of RV hypertrophy were studied. The model of RVD (SU5416/hypoxia) exhibited a significantly decreased gene expression of peroxisome proliferator-activated receptor-gamma coactivator-1alpha, peroxisome proliferator-activated receptor-alpha and estrogen-related receptor-alpha. The expression of multiple peroxisome proliferator-activated receptor-gamma coactivator-1alpha target genes required for fatty acid oxidation was similarly decreased. Decreased peroxisome proliferator-activated receptor-gamma coactivator-1alpha expression was also associated with a net loss of mitochondrial protein and oxidative capacity. Reduced mitochondrial number was associated with a downregulation of transcription factor A, mitochondrial, and other genes required for mitochondrial biogenesis. Electron microscopy demonstrated that, in RVD tissue, mitochondria had abnormal shape and size. Lastly, respirometric analysis demonstrated that mitochondria isolated from RVD tissue had a significantly reduced ADP-stimulated (state 3) rate for complex I. Conversely, functional RV hypertrophy in the pulmonary artery banding model showed normal expression of peroxisome proliferator-activated receptor-gamma coactivator-1alpha, whereas the expression of fatty acid oxidation genes was either preserved or unregulated. Moreover, pulmonary artery banding-RV tissue exhibited preserved transcription factor A mitochondrial expression and mitochondrial respiration despite elevated RV pressure-overload. CONCLUSIONS: Right ventricular dysfunction, but not functional RV hypertrophy in rats, demonstrates a gene expression profile compatible with a multilevel impairment of fatty acid metabolism and significant mitochondrial dysfunction, partially independent of chronic pressure-overload.

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CRRD Object Information
CRRD ID: 7242015
Created: 2013-03-20
Species: All species
Last Modified: 2013-03-20
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.