A RASSF1A-HIF1α loop drives Warburg effect in cancer and pulmonary hypertension.
Dabral Swati,Muecke Christian,Valasarajan Chanil,Schmoranzer Mario,Wietelmann Astrid,Semenza Gregg L,Meister Michael,Muley Thomas,Seeger-Nukpezah Tamina,Samakovlis Christos,Weissmann Norbert,Grimminger Friedrich,Seeger Werner,Savai Rajkumar,Pullamsetti Soni S
Hypoxia signaling plays a major role in non-malignant and malignant hyperproliferative diseases. Pulmonary hypertension (PH), a hypoxia-driven vascular disease, is characterized by a glycolytic switch similar to the Warburg effect in cancer. Ras association domain family 1A (RASSF1A) is a scaffold protein that acts as a tumour suppressor. Here we show that hypoxia promotes stabilization of RASSF1A through NOX-1- and protein kinase C- dependent phosphorylation. In parallel, hypoxia inducible factor-1 α (HIF-1α) activates RASSF1A transcription via HIF-binding sites in the RASSF1A promoter region. Vice versa, RASSF1A binds to HIF-1α, blocks its prolyl-hydroxylation and proteasomal degradation, and thus enhances the activation of the glycolytic switch. We find that this mechanism operates in experimental hypoxia-induced PH, which is blocked in RASSF1A knockout mice, in human primary PH vascular cells, and in a subset of human lung cancer cells. We conclude that RASSF1A-HIF-1α forms a feedforward loop driving hypoxia signaling in PH and cancer.
Multi-omic meta-analysis identifies functional signatures of airway microbiome in chronic obstructive pulmonary disease.
Wang Zhang,Yang Yuqiong,Yan Zhengzheng,Liu Haiyue,Chen Boxuan,Liang Zhenyu,Wang Fengyan,Miller Bruce E,Tal-Singer Ruth,Yi Xinzhu,Li Jintian,Stampfli Martin R,Zhou Hongwei,Brightling Christopher E,Brown James R,Wu Martin,Chen Rongchang,Shu Wensheng
The ISME journal
The interaction between airway microbiome and host in chronic obstructive pulmonary disease (COPD) is poorly understood. Here we used a multi-omic meta-analysis approach to characterize the functional signature of airway microbiome in COPD. We retrieved all public COPD sputum microbiome datasets, totaling 1640 samples from 16S rRNA gene datasets and 26 samples from metagenomic datasets from across the world. We identified microbial taxonomic shifts using random effect meta-analysis and established a global classifier for COPD using 12 microbial genera. We inferred the metabolic potentials for the airway microbiome, established their molecular links to host targets, and explored their effects in a separate meta-analysis on 1340 public human airway transcriptome samples for COPD. 29.6% of differentially expressed human pathways were predicted to be targeted by microbiome metabolism. For inferred metabolite-host interactions, the flux of disease-modifying metabolites as predicted from host transcriptome was generally concordant with their predicted metabolic turnover in microbiome, suggesting a synergistic response between microbiome and host in COPD. The meta-analysis results were further validated by a pilot multi-omic study on 18 COPD patients and 10 controls, in which airway metagenome, metabolome, and host transcriptome were simultaneously characterized. 69.9% of the proposed "microbiome-metabolite-host" interaction links were validated in the independent multi-omic data. Butyrate, homocysteine, and palmitate were the microbial metabolites showing strongest interactions with COPD-associated host genes. Our meta-analysis uncovered functional properties of airway microbiome that interacted with COPD host gene signatures, and demonstrated the possibility of leveraging public multi-omic data to interrogate disease biology.
Pulmonary hypertension in chronic obstructive pulmonary disease.
Gredic Marija,Blanco Isabel,Kovacs Gabor,Helyes Zsuzsanna,Ferdinandy Péter,Olschewski Horst,Barberà Joan Albert,Weissmann Norbert
British journal of pharmacology
Even mild pulmonary hypertension (PH) is associated with increased mortality and morbidity in patients with chronic obstructive pulmonary disease (COPD). However, the underlying mechanisms remain elusive; therefore, specific and efficient treatment options are not available. Therapeutic approaches tested in the clinical setting, including long-term oxygen administration and systemic vasodilators, gave disappointing results and might be only beneficial for specific subgroups of patients. Preclinical studies identified several therapeutic approaches for the treatment of PH in COPD. Further research should provide deeper insight into the complex pathophysiological mechanisms driving vascular alterations in COPD, especially as such vascular (molecular) alterations have been previously suggested to affect COPD development. This review summarizes the current understanding of the pathophysiology of PH in COPD and gives an overview of the available treatment options and recent advances in preclinical studies.