Dataset Information

Inhibition of fatty acid synthase is protective in pulmonary hypertension.

ABSTRACT:

Background and purpose

In pulmonary hypertension (PH), similar to cancer, there is altered energy metabolism, apoptosis resistance and cellular proliferation leading to pulmonary vascular remodelling. Proliferating cells exhibit higher rate of de novo fatty acid synthesis to provide lipids for membrane formation and energy production. As inhibition of de novo fatty acid synthesis proved protective in cancer experimentally, therefore, it was hypothesized that modulation of de novo fatty acid synthesis by inhibition of fatty acid synthase (FAS) may prove beneficial for PH.

Experimental approach

For in vitro studies, human pulmonary artery smooth muscle cells (HPASMCs) were exposed to hypoxia and to induce PH in vivo, rats were treated with monocrotaline (MCT). FAS was inhibited by siRNA (60 nM) and C75 (2 mg·kg(-1) , i.p. once a week for 5 weeks) in in vitro and in vivo studies respectively.

Results

Increased expression and activity of FAS were observed in hypoxic HPASMCs and lungs of MCT-treated rats. Inhibition of FAS increased apoptosis and glucose oxidation, but decreased proliferation and markers of autophagy, glycolysis and insulin resistance in hypoxic HPASMCs. It also improved the mitochondrial functions as evident by increased level of ATP and restoration of normal level of ROS and membrane potential of mitochondria. In MCT-treated rats, FAS inhibition decreased right ventricular pressure, hypertrophy, pulmonary vascular remodelling (increased apoptosis and decreased proliferation of cells) and endothelial dysfunction in lungs.

Conclusions

Our results demonstrate that FAS activity is modulated in PH, and its inhibition may provide a new therapeutic approach to treat PH.

SUBMITTER: Singh N

PROVIDER: S-EPMC4882492 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Publications

Inhibition of fatty acid synthase is protective in pulmonary hypertension.

Singh Neetu N Manhas Amit A Kaur Gurpreet G Jagavelu Kumaravelu K Hanif Kashif K

British journal of pharmacology 20160513 12

<h4>Background and purpose</h4>In pulmonary hypertension (PH), similar to cancer, there is altered energy metabolism, apoptosis resistance and cellular proliferation leading to pulmonary vascular remodelling. Proliferating cells exhibit higher rate of de novo fatty acid synthesis to provide lipids for membrane formation and energy production. As inhibition of de novo fatty acid synthesis proved protective in cancer experimentally, therefore, it was hypothesized that modulation of de novo fatty a ...[more]

PMID: 27061087

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Project description:Pulmonary arterial hypertension describes a group of diseases characterised by raised pulmonary vascular resistance, resulting from vascular remodelling in the pre-capillary resistance arterioles. Left untreated, patients die from right heart failure. Pulmonary vascular remodelling involves all cell types but to date the precise roles of the different cells is unknown. This study investigated differences in basal gene expression between pulmonary arterial hypertension and controls using both human pulmonary microvascular endothelial cells and human pulmonary artery smooth muscle cells. Human pulmonary microvascular endothelial cells and human pulmonary artery smooth muscle cells from pulmonary arterial hypertension patients and controls were cultured to confluence, harvested and RNA extracted. Whole genome sequencing was performed and after transcript quantification and normalisation, we examined differentially expressed genes and applied gene set enrichment analysis to the differentially expressed genes to identify putative activated pathways. Human pulmonary microvascular endothelial cells displayed 1008 significant (p ≤ 0.0001) differentially expressed genes in pulmonary arterial hypertension samples compared to controls. In human pulmonary artery smooth muscle cells, there were 229 significant (p ≤ 0.0001) differentially expressed genes between pulmonary arterial hypertension and controls. Pathway analysis revealed distinctive differences: human pulmonary microvascular endothelial cells display down-regulation of extracellular matrix organisation, collagen formation and biosynthesis, focal- and cell-adhesion molecules suggesting severe endothelial barrier dysfunction and vascular permeability in pulmonary arterial hypertension pathogenesis. In contrast, pathways in human pulmonary artery smooth muscle cells were mainly up-regulated, including those for fatty acid metabolism, biosynthesis of unsaturated fatty acids, cell-cell and adherens junction interactions suggesting a more energy-driven proliferative phenotype. This suggests that the two cell types play different mechanistic roles in pulmonary arterial hypertension pathogenesis and further studies are required to fully elucidate the role each plays and the interactions between these cell types in vascular remodelling in disease progression.

Dataset Information

Inhibition of fatty acid synthase is protective in pulmonary hypertension.

Background and purpose

Experimental approach

Results

Conclusions

Publications

Inhibition of fatty acid synthase is protective in pulmonary hypertension.

Similar Datasets

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