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Targeting cyclin-dependent kinases for the...

May 2019

Nat Commun. 2019 May 17;10(1):2204. doi: 10.1038/s41467-019-10135-x.

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

Weiss A, Neubauer MC, Yerabolu D, Kojonazarov B, Schlueter BC, Neubert L, Jonigk D, Baal N, Ruppert C, Dorfmuller P, Pullamsetti SS, Weissmann N, Ghofrani HA, Grimminger F, Seeger W, Schermuly RT.

Pulmonary arterial hypertension (PAH) is a devastating disease with poor prognosis and limited therapeutic options. Current vasodilator treatment approaches address the increased vascular tone but are not able to reverse the proliferative changes in the vascular wall. A screening for pathways that may be responsible for the abnormal phenotype of pulmonary arterial smooth muscle cells (PASMCs), a major contributor of PAH pathobiology, identified cyclin-dependent kinases (CDKs) as over-activated kinases in specimens derived from patients with idiopathic PAH. This increased CDK activity was confirmed at the level of mRNA and protein expression in human and experimental PAH, respectively. Specific CDK inhibition by the small molecule inhibitors dinaciclib and palbociclib decreased 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), the clinically approved CDK inhibitor palbociclib reversed elevated right ventricular systolic pressure, reduced right heart hypertrophy, restored cardiac index, and reduced pulmonary vascular remodeling (figure). These results demonstrate that inhibition of CDKs by palbociclib may be a therapeutic strategy for PAH and the strong anti-proliferative profile of this CDK inhibitor suggests that this molecule has the necessary properties to allow further investigation of its therapeutic benefit in PAH patients.

Figure: Reversal of structural remodeling due to palbociclib administration in the Su/Hox model of PAH. The degree of muscularization of small pulmonary arteries was determined ex vivo via immunhistological staining of lung sections for vWF (brown) and α-SMA (violet) together with methylgreen for counterstaining. M: fully muscularized; P: partially muscularized; N: non-muscularized. An improvement in pulmonary vascular remodeling (reverse remodeling) was clearly demonstrated by a reduction in the percentage of fully muscularized small pulmonary arteries after palbociclib treatment (palbo). These effects are a direct consequence of a targeted cell cycle arrest and subsequent inhibition of pulmonary vascular cell proliferation.