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Metabolic Dysfunction in Pulmonary Arterial Hypertension.

ABSTRACT: Previously considered a disease isolated to the pulmonary circulation, pulmonary arterial hypertension is now being recognized as a systemic disorder that is associated with significant metabolic dysfunction. Numerous animal models have demonstrated the development of pulmonary arterial hypertension following the onset of insulin resistance, indicating that insulin resistance may be causal. Recent publications highlighting alterations in aerobic glycolysis, fatty acid oxidation, and the tricarboxylic acid cycle in the pulmonary circulation and right ventricle have expanded our understanding of the complex pathobiology of this disease. By targeting these derangements in metabolism, numerous researchers are investigating noninvasive techniques to monitor disease activity and therapeutics that address the underlying metabolic condition. In the following review, we will explore pre-clinical and clinical studies investigating the metabolic dysfunction seen in pulmonary arterial hypertension.

SUBMITTER: Assad TR

PROVIDER: S-EPMC4840894 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Metabolic Dysfunction in Pulmonary Arterial Hypertension.

Assad Tufik R TR Hemnes Anna R AR

Current hypertension reports 20150301 3

Previously considered a disease isolated to the pulmonary circulation, pulmonary arterial hypertension is now being recognized as a systemic disorder that is associated with significant metabolic dysfunction. Numerous animal models have demonstrated the development of pulmonary arterial hypertension following the onset of insulin resistance, indicating that insulin resistance may be causal. Recent publications highlighting alterations in aerobic glycolysis, fatty acid oxidation, and the tricarbo ...[more]

PMID: 25754317

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Project description: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.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-? coactivator-1?, peroxisome proliferator-activated receptor-? and estrogen-related receptor-?. The expression of multiple peroxisome proliferator-activated receptor-? coactivator-1? target genes required for fatty acid oxidation was similarly decreased. Decreased peroxisome proliferator-activated receptor-? coactivator-1? 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-? coactivator-1?, 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.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.

Dataset Information

Metabolic Dysfunction in Pulmonary Arterial Hypertension.

Publications

Metabolic Dysfunction in Pulmonary Arterial Hypertension.

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