Targeting cyclin-dependent kinases for the treatment of pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a devastating disease with poor prognosis and limited therapeutic options. We screened for pathways that may be responsible for the abnormal phenotype of pulmonary arterial smooth muscle cells (PASMCs), a major contributor of PAH pathobiology, and identified...

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Published in:	Nature communications Vol. 10; no. 1; pp. 2204 - 17
Main Authors:	Weiss, Astrid, Neubauer, Moritz Christian, Yerabolu, Dinesh, Kojonazarov, Baktybek, Schlueter, Beate Christiane, Neubert, Lavinia, Jonigk, Danny, Baal, Nelli, Ruppert, Clemens, Dorfmuller, Peter, Pullamsetti, Soni Savai, Weissmann, Norbert, Ghofrani, Hossein-Ardeschir, Grimminger, Friedrich, Seeger, Werner, Schermuly, Ralph Theo
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 17-05-2019 Nature Publishing Group Nature Portfolio
Subjects:	13/2 13/31 13/51 13/95 38/77 38/79 692/308/153 692/699/75 9/25 96/1 96/63 Animals Blood pressure Cancer Cell cycle Cell Line Cyclin-dependent kinase Cyclin-dependent kinases Cyclin-Dependent Kinases - antagonists & inhibitors Cyclin-Dependent Kinases - metabolism Disease control Disease Models, Animal E2F protein Familial Primary Pulmonary Hypertension - chemically induced Familial Primary Pulmonary Hypertension - drug therapy Familial Primary Pulmonary Hypertension - pathology Familial Primary Pulmonary Hypertension - surgery Gene expression Heart Humanities and Social Sciences Humans Hypertension Hypertrophy Hypoxia Indoles - toxicity Inhibition Kinases Lung - blood supply Lung - pathology Lung - surgery Male Mice Mice, Inbred C57BL Monocrotaline Monocrotaline - toxicity mRNA multidisciplinary Muscle, Smooth, Vascular - cytology Muscle, Smooth, Vascular - pathology Muscles Myocytes, Smooth Muscle - drug effects Myocytes, Smooth Muscle - pathology Phenotypes Piperazines - pharmacology Piperazines - therapeutic use Protein Kinase Inhibitors - pharmacology Protein Kinase Inhibitors - therapeutic use Proteins Pulmonary Artery - cytology Pulmonary Artery - drug effects Pulmonary Artery - pathology Pulmonary hypertension Pyridines - pharmacology Pyridines - therapeutic use Pyrroles - toxicity Rats Rats, Inbred WKY Rats, Sprague-Dawley Retina Retinoblastoma Retinoblastoma protein Science Science (multidisciplinary) Signal transduction Smooth muscle Systolic pressure Treatment Outcome Ventricle
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Summary:	Pulmonary arterial hypertension (PAH) is a devastating disease with poor prognosis and limited therapeutic options. We screened for pathways that may be responsible for the abnormal phenotype of pulmonary arterial smooth muscle cells (PASMCs), a major contributor of PAH pathobiology, and identified cyclin-dependent kinases (CDKs) as overactivated kinases in specimens derived from patients with idiopathic PAH. This increased CDK activity is confirmed at the level of mRNA and protein expression in human and experimental PAH, respectively. Specific CDK inhibition by dinaciclib and palbociclib decreases PASMC proliferation via cell cycle arrest and interference with the downstream CDK-Rb (retinoblastoma protein)-E2F signaling pathway. In two experimental models of PAH (i.e., monocrotaline and Su5416/hypoxia treated rats) palbociclib reverses the elevated right ventricular systolic pressure, reduces right heart hypertrophy, restores the cardiac index, and reduces pulmonary vascular remodeling. These results demonstrate that inhibition of CDKs by palbociclib may be a therapeutic strategy in PAH. Cells of the pulmonary vasculature show a hyperproliferative phenotype in pulmonary arterial hypertension (PAH), thus contributing to the disease pathogenesis. Here the authors show that cyclin-dependent kinases are overactivated in PAH, and that their pharmacological inhibition attenuates the disease in two independent rodent models
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-019-10135-x