+1 Recommend
0 collections
      • Record: found
      • Abstract: not found
      • Article: not found

      Multicenter Preclinical Validation of BET Inhibition for the Treatment of Pulmonary Arterial Hypertension

      Read this article at

          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Related collections

          Most cited references 21

          • Record: found
          • Abstract: found
          • Article: not found

          Targeting polo-like kinase 1 for cancer therapy.

          Human polo-like kinase 1 (PLK1) is essential during mitosis and in the maintenance of genomic stability. PLK1 is overexpressed in human tumours and has prognostic potential in cancer, indicating its involvement in carcinogenesis and its potential as a therapeutic target. The use of different PLK1 inhibitors has increased our knowledge of mitotic regulation and allowed us to assess their ability to suppress tumour growth in vivo. We address the structural features of the kinase domain and the unique polo-box domain of PLK1 that are most suited for drug development and discuss our current understanding of the therapeutic potential of PLK1.
            • Record: found
            • Abstract: found
            • Article: not found

            BET bromodomain inhibition suppresses innate inflammatory and profibrotic transcriptional networks in heart failure

            Despite current standard of care, the average 5-year mortality after an initial diagnosis of heart failure (HF) is about 40%, reflecting an urgent need for new therapeutic approaches. Previous studies demonstrated that the epigenetic reader protein bromodomain-containing protein 4 (BRD4), an emerging therapeutic target in cancer, functions as a critical coactivator of pathologic gene transactivation during cardiomyocyte hypertrophy. However, the therapeutic relevance of these findings to human disease remained unknown. We demonstrate that treatment with the BET bromodomain inhibitor JQ1 has therapeutic effects during severe, preestablished HF from prolonged pressure overload, as well as after a massive anterior myocardial infarction in mice. Furthermore, JQ1 potently blocks agonist-induced hypertrophy in human induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs). Integrated transcriptomic analyses across animal models and human iPSC-CMs reveal that BET inhibition preferentially blocks transactivation of a common pathologic gene regulatory program that is robustly enriched for NFB and TGF-β signaling networks, typified by innate inflammatory and profibrotic myocardial genes. As predicted by these specific transcriptional mechanisms, we found that JQ1 does not suppress physiological cardiac hypertrophy in a mouse swimming model. These findings establish that pharmacologically targeting innate inflammatory and profibrotic myocardial signaling networks at the level of chromatin is effective in animal models and human cardiomyocytes, providing the critical rationale for further development of BET inhibitors and other epigenomic medicines for HF.
              • Record: found
              • Abstract: found
              • Article: found
              Is Open Access

              TNFα drives pulmonary arterial hypertension by suppressing the BMP type-II receptor and altering NOTCH signalling

              Heterozygous germ-line mutations in the bone morphogenetic protein type-II receptor (BMPR-II) gene underlie heritable pulmonary arterial hypertension (HPAH). Although inflammation promotes PAH, the mechanisms by which inflammation and BMPR-II dysfunction conspire to cause disease remain unknown. Here we identify that tumour necrosis factor-α (TNFα) selectively reduces BMPR-II transcription and mediates post-translational BMPR-II cleavage via the sheddases, ADAM10 and ADAM17 in pulmonary artery smooth muscle cells (PASMCs). TNFα-mediated suppression of BMPR-II subverts BMP signalling, leading to BMP6-mediated PASMC proliferation via preferential activation of an ALK2/ACTR-IIA signalling axis. Furthermore, TNFα, via SRC family kinases, increases pro-proliferative NOTCH2 signalling in HPAH PASMCs with reduced BMPR-II expression. We confirm this signalling switch in rodent models of PAH and demonstrate that anti-TNFα immunotherapy reverses disease progression, restoring normal BMP/NOTCH signalling. Collectively, these findings identify mechanisms by which BMP and TNFα signalling contribute to disease, and suggest a tractable approach for therapeutic intervention in PAH.

                Author and article information

                American Journal of Respiratory and Critical Care Medicine
                Am J Respir Crit Care Med
                American Thoracic Society
                October 01 2019
                October 01 2019
                : 200
                : 7
                : 910-920
                [1 ]Center for Congenital Heart Diseases, Beatrix Children’s Hospital, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
                [2 ]Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands
                [3 ]Pulmonary Hypertension and Vascular Biology Research Group of Quebec Heart and Lung Institute, Laval University, Quebec, Canada
                [4 ]Pulmonary Medicine, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, Amsterdam, the Netherlands
                [5 ]Reseverlogix Calgary, Calgary, Alberta, Canada; and
                [6 ]Division of Cardiology, Department of Pediatrics, Erasmus University Medical Center, Sophia Children’s Hospital, Rotterdam, the Netherlands
                © 2019


                Comment on this article