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

Astrid Weiss, Moritz Christian Neubauer, Dinesh Yerabolu, Baktybek Kojonazarov, Beate Christiane Schlueter, Lavinia Neubert, Danny Jonigk, Nelli Baal, Clemens Ruppert, Peter Dorfmuller, Soni Savai Pullamsetti, Norbert Weissmann, Hossein-Ardeschir Ghofrani, Friedrich Grimminger, Werner Seeger and Ralph Theo Schermuly ()
Additional contact information
Astrid Weiss: Justus-Liebig-University Giessen (JLU)
Moritz Christian Neubauer: Justus-Liebig-University Giessen (JLU)
Dinesh Yerabolu: Justus-Liebig-University Giessen (JLU)
Baktybek Kojonazarov: Justus-Liebig-University Giessen (JLU)
Beate Christiane Schlueter: Justus-Liebig-University Giessen (JLU)
Lavinia Neubert: Member of the German Center for Lung Research (DZL)
Danny Jonigk: Member of the German Center for Lung Research (DZL)
Nelli Baal: Justus-Liebig-University Giessen (JLU)
Clemens Ruppert: Justus-Liebig-University Giessen (JLU)
Peter Dorfmuller: Member of the German Center for Lung Research (DZL)
Soni Savai Pullamsetti: Universities of Giessen and Marburg Lung Center (UGMLC)
Norbert Weissmann: Justus-Liebig-University Giessen (JLU)
Hossein-Ardeschir Ghofrani: Justus-Liebig-University Giessen (JLU)
Friedrich Grimminger: Justus-Liebig-University Giessen (JLU)
Werner Seeger: Justus-Liebig-University Giessen (JLU)
Ralph Theo Schermuly: Justus-Liebig-University Giessen (JLU)

Nature Communications, 2019, vol. 10, issue 1, 1-17

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-10135-x

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