Uncovering of signaling pathway regulating changes in energy metabolism during development of pulmonary hypertension
Pulmonary hypertension is a syndrome characterized by high blood pressure in pulmonary circulation. This is often accompanied by some serious diseases and can be eventually fatal. A pulmonary artery remodeling involving all layers of artery wall thus leading to artery wall hypertrophy is fundamental to pulmonary arterial hypertension development.
Scientists of the Departmentof Mitochondrial Physiology of the Institute of Physiology CAS in collaboration with the laboratory of Prof. Stenmark from Denver University in US, have found that remodeling of pulmonary artery, specifically tunica adventitia/externa is conditioned by changes in energy metabolism from mitochondrial oxidative phosphorylation to glycolysis and increased lactate production, similarly as recognized for many cancer cells. We have uncovered regulatory pathway participating in this metabolic change. This involves inhibition of small non-coding RNA (miR-124), which induces overproduction of nuclear ribonucleoprotein PTBP1, which further leads to increased ratio of pyruvate kinase isoform2 to isoform1. The changes in isoform type of pyruvate kinase given by alternative splicing induce glycolytic pathway and at the same time reduce mitochondrial metabolism, specifically diminish mitochondrial ATP production. The primary significance of such metabolic changes is suggested increase of building components for pulmonary artery cells proliferation, which leads to hypertrophy of pulmonary artery wall during disease development. This adjustment also increases resistance to programmed cell death (apoptosis) and induces local pro-inflammatory reaction. These changes in metabolism were possible to suppress by genetic or pharmacological manipulations of participating enzymes within the pathway or by inhibition of histone deacetylases. Obtained new knowledge thus offers new suitable targets for production of potential treatment of the pulmonary hypertension.
Zhang, H. - Wang, D. - Li, M. - Plecitá-Hlavatá, Lydie - D'Alessandro, A. - Tauber, Jan - Riddle, S. - Kumar, S. - Flockton, A. - McKeon, B. A. - Frid, M. G. - Reisz, J. A. - Caruso, P. - El Kasmi, K. C. - Ježek, Petr - Morrell, N. W. - Hu, Ch.-J. - Stenmark, K. R.: Metabolic and Proliferative State of Vascular Adventitial Fibroblasts in Pulmonary Hypertension Is Regulated Through a MicroRNA-124/PTBP1 (Polypyrimidine Tract Binding Protein 1)/Pyruvate Kinase Muscle Axis. Roč. 136, č. 25 (2017), s. 2468-2485 ISSN 0009-7322