Abstract Body: Introduction:
Pulmonary arterial hypertension (PAH) is a rare and debilitating condition with a low survival rate. Elevated pulmonary pressures arise from excessive vascular remodeling of the arteries and phenotypic changes in pulmonary vascular smooth muscle cells (VSMC). Vascular remodeling in PAH has hyperproliferative and anti-apoptotic characteristics, much like cancer. Prior studies in our lab have identified a novel molecule elevated in both cancer and PAH: PBK (PDZ-Binding Kinase). Investigation into PBK reveals that upregulation of the enzyme occurs in human PAH and all models of pulmonary hypertension, and immunofluorescent imaging suggested the upregulation of PBK in the medial layer of pulmonary vasculature. We found that global knockout of PBK in rats prevented the development of pulmonary hypertension, as did total body inhibition of PBK using pharmacological agents.
Hypothesis:
Pulmonary vascular smooth muscle cell-derived upregulation of PBK is necessary for the development of pulmonary hypertension.
Results:
To determine if PBK upregulation in smooth muscle is responsible for the development of pulmonary hypertension, we crossed a floxed PBK mouse with a constitutively active smooth muscle specific cre to generate smooth muscle specific PBK knockout mice. These mice were then subjected to a Sugen hypoxia regimen to induce pulmonary hypertension, and it was found that these mice were not protected from disease development. To test if PBK was elevated in other cell types, an endothelial cell specific cre was also crossed with the floxed PBK mouse and this mouse also was not protected from pulmonary hypertension. Bone marrow transplants were performed on rats, with reconstitution of irradiated wild-type rats with PBK knockout bone marrow before inducing pulmonary hypertension using monocrotaline. These rats were found to develop less severe pulmonary hypertension compared to PBK knockout rats reconstituted with wild-type bone marrow, leading us to hypothesize that myeloid derived PBK is instrumental to pulmonary hypertension development. Most recently, the floxed PBK mouse has been crossed with a myeloid-specific cre to determine if PBK is playing a role in immune cells.
Conclusion:
While our initial hypothesis that induction of PBK in pulmonary vascular smooth muscle drives PAH was not supported by our experiments, increases in myeloid-derived PBK may be responsible for disease progression and severity.