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PBK is a Novel Regulator of Vascular Remodeling in Pulmonary Arterial Hypertension
Author(s) -
Bordan Zsuzsanna,
Chen Feng,
Li Xueyi,
Batori Robert,
Haigh Stephen,
Meadows Mary-Louise,
Singla Bupesh,
Csanyi Gabor,
Su Yunchao Karoly,
Barman Scott Karoly,
Fulton David
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.06128
Subject(s) - cancer research , pulmonary hypertension , hypoxia (environmental) , lung cancer , cancer , kinase , medicine , pulmonary artery , endocrinology , vascular smooth muscle , biology , chemistry , smooth muscle , microbiology and biotechnology , organic chemistry , oxygen
Pulmonary Arterial Hypertension (PAH) is an insidious disease that develops gradually and becomes symptomatic only in the latter stages. In PAH, along with increased pulmonary artery (PA) pressure, the PAs in the lungs continue to become more muscular, narrower restricting blood flow through the lungs. Increased proliferation of pulmonary arterial smooth muscle cells (PASMC) are largely responsible for the development PA hypertrophy. Because excessive proliferation of PASMC in PAH shares many characteristics with other hyperproliferative diseases such as cancer, there is a growing interest in repurposing therapeutic targets in cancer, for the treatment of PAH. In preliminary studies, we screened a microarray of isolated PAs from control and monocrotaline (MCT)‐induced PAH rats for novel genes that may be responsible for the proliferation of PASMCs in PAH. We found that the gene PDZ‐Binding Kinase (PBK) was significantly higher in PAs from MCT rats versus controls. PBK (also known as TOPK or T‐cell‐originated Lymphokine‐activated killer protein kinase) is a serine/threonine kinase that plays a key role in several types of cancer. Although PBK levels are typically very low in healthy tissues, expression levels are significantly increased in cancer cells, which correlates with a poor prognosis of breast, gastric and lung cancers. We performed immunostaining, and found that PBK was highly upregulated and concentrated in the smooth muscle layer of both PAH rats (MCT and Sugen/Hypoxia induced) as well as in human PAs with PAH. To determine a functional role for PBK in PASMCs, we generated an adenovirus encoding PBK and found that increased expression stimulated PASMC proliferation and resistance to apoptosis. In contrast, silencing PBK or in vitro pharmacological inhibition (HI‐TOPK‐032, 2μM) significantly (p<0.05; n=5) reduced PASMC proliferation and increased cell death. Furthermore, the specific PBK inhibitor OTS514 (5mg/kg/day for 14 days) reduced right ventricle hypertrophy (Fulton Index) and improved PA remodeling in the MCT‐induced model of PAH. Collectively, these findings suggest that PBK drives pulmonary artery smooth muscle proliferation leading to abnormal vascular remodeling and the development of PAH. Support or Funding Information AHA 19PRE34450087 R01HL125926‐03