Role of CHK1 in Pulmonary Arterial Hypertension
Background:Â Pulmonary arterial hypertension (PAH) is a vascular remodeling disease characterized by a by progressive obliteration of the small pulmonary arteries (PAs) due to excessive proliferation and resistance to apoptosis of PA smooth muscle cells (PASMCs). Given that PAH and cancer cells share similarities, this opens the possibility of exploiting therapeutic agents used in cancer to treat PAH. Cancer cells presenting intrinsic elevated replication stress (RS) rely on activation of the CHK1 pathway to restrain the accumulation of deleterious levels of DNA damage.
Objective:Â We hypothesize that PAH-PASMCs have developed an orchestrated response mediated by CHK1 to overcome RS/DNA damage, allowing cell survival and proliferation.
Methods and Results:Â Using Western blot (WB), we demonstrated that, compared to control cells, isolated PAH-PASMCs display elevated expression of RS/DNA damage markers (WB pRPA32 and Î³H2AX, p<0.05). This is associated with increased expression and activation of CHK1 (WB, p<0.01).Â In vitro, we provide evidence that decreased miR-424 expression (qPCR, p<0.05) accounts for CHK1 up-regulation in PAH-PASMCs. Molecular (siCHK1) and pharmacological (MK-8776) inhibition of CHK1 exacerbates the levels of RS and DNA damage leading to reduced PAH-PASMC viability (MTT assay, p<0.05), proliferation (Ki67 labeling, p<0.01) and resistance to apoptosis (AnnexinV assay, p<0.05). Moreover, CHK1 is increased in the monocrotaline (MCT) rat and SIV-infected macaque models of PAH.Â In vivo, MK-8776 significantly improved (p<0.01) established PAH by decreasing the mean PA pressure and PA medial wall thickness in the MCT model.
Conclusion:Â CHK1 is implicated in PAH development and represents a new promising therapeutic target.
Cite this article as: European Respiratory Journal 2018 52: Suppl. 62, PA3930.
This is an ERS International Congress abstract. No full-text version is available. Further material to accompany this abstract may be available atÂ www.ers-education.orgÂ (ERS member access only).
- Copyright Â©the authors 2018