PDZ‐Binding Kinase Drives Pulmonary Artery Smooth Muscle Proliferation and Vascular Remodeling in Pulmonary Arterial Hypertension

Abstract

Pulmonary Arterial Hypertension (PAH) is a progressive disease that is caused by high blood pressure in the lungs that originates from increased resistance of small pulmonary arteries (PA). A defining characteristic of PAH is vascular smooth muscle cell (VSMC) proliferation and remodeling of PA, that eventually results in right ventricular failure and death. The hyperproliferative nature of vascular cells in PAH shares many characteristics with cancer cells such as sustained proliferative signaling, changes in hypoxia signaling and cellular metabolism. Using microarray analysis, we discovered a novel gene, PDZ‐Binding Kinase (PBK) that is upregulated in hypertensive PA. PBK is a serine/threonine kinase that has important roles in mitosis and cell proliferation. Also, elevated expression of PBK is associated with numerous aggressive cancers suggesting that it may be an important contributor to PAH. Our hypothesis is that PBK has a functional role in the pathogenesis of PAH but the therapeutic utility of targeting PBK in PAH and the mechanisms by which PBK promotes pulmonary vascular remodeling have not been studied. To investigate the role of PBK in PAH, we performed immunostaining, and found that PBK was highly upregulated in pulmonary arterial smooth muscle in the lungs of two experimental PAH rat models (MCT; Su/H), in the Su/H mouse model, as well as in human PAs and lungs with PAH. Furthermore, human pulmonary arterial smooth cells (HPASMCs) overexpressing PBK showed increased proliferation, while silencing PBK or in vitro pharmacological inhibition significantly reduced HPASMC proliferation. To determine whether PBK plays an important role in PA remodeling and PAH in vivo, we next utilized PBK inhibitor (OTS‐514) to treat MCT‐induced PAH rats in a reversal treatment method and Su/H Rats and Mouse in a preventative treatment. In all of the PAH animal models, right ventricle (RV) thickness, velocity time integral (VTI, index of PA stiffness), right ventricular systolic pressure (RVSP), and the Fulton Index were significantly improved in the presence of the PBK inhibitor. To complement our pharmacological studies with a genetic approach, we have generated PBK KO rats to investigate whether genetic ablation of PBK protects against the development of PAH. Taken together, these data support the hypothesis, that PBK drives pulmonary artery smooth muscle proliferation leading to abnormal vascular remodeling and the development of PAH. Our findings advance the utility of novel therapeutic approaches targeting PBK to improve the morbidity and mortality associated with PAH.