Project description:Although multiple gene and protein expression have been extensively profiled in human pulmonary arterial hypertension (PAH), the mechanism for the development and progression of pulmonary hypertension remains elusive. Analysis of the global metabolomic heterogeneity within the pulmonary vascular system leads to a better understanding of disease progression. Using a combination of high-throughput liquid-and-gas-chromatography-based mass spectrometry, we showed unbiased metabolomic profiles of disrupted glycolysis, increased TCA cycle, and fatty acid metabolites with altered oxidation pathways in the severe human PAH lung. The results suggest that PAH has specific metabolic pathways contributing to increased ATP synthesis for the vascular remodeling process in severe pulmonary hypertension. These identified metabolites may serve as potential biomarkers for the diagnosis of severe PAH. By profiling metabolomic alterations of the PAH lung, we reveal new pathogenic mechanisms of PAH in its later stage, which may differ from the earlier stage of PAH, opening an avenue of exploration for therapeutics that target metabolic pathway alterations in the progression of PAH. Global profiles were determined in human lung tissue and compared across 11 normal and 12 severe pulmonary arterial hypertension patients. Using a combination of microarray and high-throughput liquid-and-gas-chromatography-based mass spectrometry, we showed unbiased metabolomic profiles of disrupted glycolysis, increased TCA cycle, and fatty acid metabolites with altered oxidation pathways in the severe human PAH lung.
Project description:Although multiple gene and protein expression have been extensively profiled in human pulmonary arterial hypertension (PAH), the mechanism for the development and progression of pulmonary hypertension remains elusive. Analysis of the global metabolomic heterogeneity within the pulmonary vascular system leads to a better understanding of disease progression. Using a combination of high-throughput liquid-and-gas-chromatography-based mass spectrometry, we showed unbiased metabolomic profiles of disrupted glycolysis, increased TCA cycle, and fatty acid metabolites with altered oxidation pathways in the severe human PAH lung. The results suggest that PAH has specific metabolic pathways contributing to increased ATP synthesis for the vascular remodeling process in severe pulmonary hypertension. These identified metabolites may serve as potential biomarkers for the diagnosis of severe PAH. By profiling metabolomic alterations of the PAH lung, we reveal new pathogenic mechanisms of PAH in its later stage, which may differ from the earlier stage of PAH, opening an avenue of exploration for therapeutics that target metabolic pathway alterations in the progression of PAH.
Project description:We determined pattern of miRNAs of mild-to-severe human pulmonary arterial hypertension and compared the with health controls using microarray and subsequently validated by QPCRs Manuscript Title: Circulating miRNAs as novel marker for pulmonary hypertension. (Under Revision Plos One Manuscript ID: PONE-D-12-38535)
Project description:We determined pattern of miRNAs of mild-to-severe human pulmonary arterial hypertension and compared the with health controls using microarray and subsequently validated by QPCRs Manuscript Title: Circulating miRNAs as novel marker for pulmonary hypertension. (Under Revision Plos One Manuscript ID: PONE-D-12-38535) Performed microRNA microarray from one healthy and one severe PH patient and compared the results using additional samples by qPCR for other miRNAs
Project description:Pulmonary arterial hypertension (PAH) is characterized by severe obstruction of small pulmonary arteries and concomitant high pulmonary arterial pressure, resulting in progressive right ventricular failure. Previously, we demonstrated that long-term interleukin (IL)-33 administration in mice induced severe occlusive arterial hypertrophy in the lung, which was mediated by group 2 innate lymphoid cells (ILC2s). In response to IL-33, ILC2s accumulated around blood vessels and produced IL-5, leading to perivascular eosinophil recruitment. In this study, we further characterized IL-33-induced pulmonary arterial hypertrophy. We first demonstrated that long-term IL-33 administration caused an increase in the right ventricular pressure. In IL-33 deficient mice, pulmonary arterial hypertrophy mediated by eggs of Schistosoma mansoni (S. mansoni) was attenuated, accompanied with partial reduction in ILC2s, eosinophils and CD4+ T cells. In addition, proteomic analysis revealed dramatic changes in urine samples from mice treated with IL-33 or S. mansoni eggs. Resistin like alpha (RELM), a pulmonary hypertension-related molecule, in the urine was commonly detected in both treatments. Large amounts of RELM were observed in the lung from IL-33-treated mice. These observations support that IL-33-induced pulmonary arterial hypertrophy is a useful model to study the mechanism underlying development of PAH and expolar biomarkers to indicate the onset of PAH.
Project description:One current concept suggests that unchecked proliferation of clonally selected precursors of endothelial cells contribute to severe pulmonary arterial hypertension (pAH). We hypothesized that clonally selected ECs expressing the progenitor marker CD117 promote severe occlusive pulmonary hypertension (PH). We used microarrays to identify the steady state gene expression profile of quaternary clones derived from CD117+ rat lung ECs vs control ECs derived from rat lung CD117- cells.