Pulmonary arterial hypertension (PAH), a disease of the small pulmonary arteries, is characterized by pulmonary vasoconstriction, vascular cell proliferation, and remodeling leading to right ventricular hypertrophy and failure. Despite advances in understanding and treatment, disease management and prognosis remain grim. Current therapies for PAH focus on restoring proper vascular tone via vasodilatory mechanisms. However, these therapies fall short and do not reverse outcome. Therefore, there is a critical need to better understand the mechanisms underlying cellular remodeling and subsequent reduction of luminal area in pulmonary arteries that lead to increased vascular resistance. In cases of heritable disease with familial origin, mutations in the bone morphogenetic protein receptor 2 (BMPR2) predispose individuals to development of PAH. Recent studies show an increase in TGFbeta-1 levels and signaling in PAH, and BMPR2 mutations may lead to increased TGFbeta signaling. Increases in TGFbeta signaling associated with decreased BMPR2 expression can promote cellular reprogramming and vascular remodeling. Evidence implicates the FK506-binding protein 51 (FKBP51) as a major regulator of cellular remodeling in metastatic melanoma and other cancers. Additionally, TGFbeta-1, known as a major player in cellular transdifferentiation, stimulates cellular reprogramming in pulmonary artery endothelial cells (PAECs), and a cooperative relationship between TGFbeta and FKBP51 has been shown in malignant cell progression. Our preliminary work indicates increased expression of FKBP51 in PAECs in a rat model of PAH. Additionally, treatment of PAECs with TGFbeta-1 increased FKBP51 levels. Overexpression of FKBP51 in PAECs led to an increase in secretion of TGFbeta. Finally, in BMPR2-deficient PAECs, FKBP51 and alpha-smooth muscle actin levels were elevated in comparison to control. Taken together, we hypothesize that in PAECs of PAH, and notably in cases of BMPR2 deficiency, FKBP51 is upregulated, increasing TGFbeta in a positive-feedback loop, resulting in the hallmark pro-proliferative, constrictive phenotype of PAH. The hypothesis will be tested with two specific aims, developed to engage medical students, and Aim 3 outlines student involvement. Specific aim 1 will characterize the expression of FKBP51 in PAECs in response to TGFbeta. Specific aim 2 will investigate the relationship of TGFbeta, FKBP51, and other inflammatory molecules such as NFkB.
|Program type||AHA Institutional Research Enhancement Award (AIRE|
|Effective start/end date||07/01/2017 → 05/31/2018|