Abstract
Although multiple, complex molecular studies have been done for understanding the development and progression of pulmonary hypertension (PAH), little is known about the metabolic heterogeneity of PAH. Using a combination of high-throughput liquid-and-gas-chromatography-based mass spectrometry, we found bile acid metabolites, which are normally product derivatives of the liver and gallbladder, were highly increased in the PAH lung. Microarray showed that the gene encoding cytochrome P450 7B1 (CYP7B1), an isozyme for bile acid synthesis, was highly expressed in the PAH lung compared with the control. CYP7B1 protein was found to be primarily localized on pulmonary vascular endothelial cells suggesting de novo bile acid synthesis may be involved in the development of PAH. Here, by profiling the metabolomic heterogeneity of the PAH lung, we reveal a newly discovered pathogenesis mechanism of PAH.Electronic supplementary materialThe online version of this article (doi:10.1007/s11306-014-0653-y) contains supplementary material, which is available to authorized users.
Highlights
Microarray showed that the gene encoding cytochrome P450 7B1 (CYP7B1), an isozyme for bile acid synthesis, was highly expressed in the pulmonary hypertension (PAH) lung compared with the control
Pulmonary arterial hypertension (PAH) is a severe vascular disease characterized by persistent precapillary pulmonary hypertension (PH) (Stacher et al 2012; International PPHC et al 2000; Zhao et al 2002; Fujiwara et al 2008; Nasim et al 2011; Olschewski 2010; Bogaard et al 2012; MMea and 2013), which can be either be idiopathic
Our recent work showed that disrupted glycolysis, increased TCA cycle, and fatty acid metabolites with altered oxidation pathways exited in the human PAH lung, indicating that PAH has specific metabolic pathways contributing to abnormal ATP synthesis for the vascular remodeling process in pulmonary hypertension (Zhao et al 2014)
Summary
Pulmonary arterial hypertension (PAH) is a severe vascular disease characterized by persistent precapillary pulmonary hypertension (PH) (Stacher et al 2012; International PPHC et al 2000; Zhao et al 2002; Fujiwara et al 2008; Nasim et al 2011; Olschewski 2010; Bogaard et al 2012; MMea and 2013), which can be either be idiopathic (sporadic90 %, familial-10 %). Evidence in the literature suggests that metabolic pathway abnormalities characterize and may play a significant role in the development and progression of PAH (Fessel et al 2012). Vascular changes under chronic hypoxic condition has been directly linked to an imbalance between glycolysis, glucose oxidation, and fatty acid oxidation (Sutendra et al 2010), while in vitro pulmonary arterial endothelial cell culture with disruption of the Bone Morphogenetic Protein Receptor II (BMPRII) gene showed significant metabolomic changes (Fessel et al 2012). Our recent work showed that disrupted glycolysis, increased TCA cycle, and fatty acid metabolites with altered oxidation pathways exited in the human PAH lung, indicating that PAH has specific metabolic pathways contributing to abnormal ATP synthesis for the vascular remodeling process in pulmonary hypertension (Zhao et al 2014). We provide direct evidence of a novel increase in bile acid metabolites in PAH lung tissue associated with the elevated expression of bile acid synthesis related transcripts, indicating de novo synthesis of bile acids may characterize and contribute to the pathogenesis of PAH
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