Abstract
Pulmonary arterial hypertension (PAH) is a progressive cardiovascular-disease with high mortality lacking high-efficiency drug. Our efforts attempted to delineate therapeutic action of osthole produced by Angelica Pubescens Maxim, which has the capacity to treat PAH by exploiting an iTRAQ-based proteomic method. Excitingly, osthole was observed to significantly restore 98 of 315 differential proteins significantly modified by PAH progression. They were primarily annotated into 24 signaling pathways. Four mostly affected proteins (RPL15, Cathepsin S, Histone H3.3 and HMGB1) were experimentially validated which belonged to ribosome pathway, oxidative phosphorylation pathway, systemic lupus erythematosus pathway, complement and coagulation cascades pathway, whose modifications and modulations mostly accounted for therapeutic capacity of this compound against PAH. Altogether, our findings demonstrated that global proteomics is a promising systems-biology approach for deciphering therapeutic actions and associated mechanisms of natural products derived from traditional Chinese medicine. Importantly, osthole is supposed to be a candidate compound for new drug development to treat PAH.
Highlights
Over the past twenty years, there are nine selected drugs that are observed to be efficient for treating Pulmonary arterial hypertension (PAH) by targeting the known signaling pathways of endothelin, nitric oxide and prostacyclin, respectively
These results suggested that osthole greatly reversed the increased pulmonary arterial pressure and right ventricular hypertrophy caused by PAH progression
Four proteins as Histone H3.3, High-mobility group protein B1 (HMGB1), ribosomal protein L15 (RPL15) and Cathepsin S were significantly regulated by osthole treatment, those proteins might have the capacity for better understanding of the pathogenesis of PAH and therapeutic discovery of osthole
Summary
Over the past twenty years, there are nine selected drugs that are observed to be efficient for treating PAH by targeting the known signaling pathways of endothelin, nitric oxide and prostacyclin, respectively. Systems biology driven proteomics method is being emerged as a powerful and robust tool for recognizing and characterizing differential proteins associated with differently physiological and pathological events or processes, by which we can discover and identify protein biomarkers for disease diagnosis, as well as interrogate potentially therapeutic targets for drug discovery and development[10] This method is increasingly employed to investigate pharmacological actions and associated mechanisms of Chinese herbal medicines from proteome perspective[11]. Global proteome assay further demonstrated that osthole was observed to significantly restore the modifications of Histone H3.3, High-mobility group protein B1 (HMGB1), Cathepsin S, and 60S ribosomal protein L15 (RPL15) during PAH progression Those mostly affected proteins were covered by several key signaling pathways involving ribosome pathway, oxidative phosphorylation pathway, systemic lupus erythematosus pathway, complement and coagulation cascades pathway as this compound has the capacity to treat PAH by improving the modifications with those key pathways. Our findings manifested that global proteome method is supposed to be a promising approach for assessing systems actions of natural products and verified osthole could be a candidate compound for new drug discovery to treat PAH in clinic
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