Pin'ning down endothelial dysfunction and thrombosis in chronic thromboembolic pulmonary hypertension

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare complication of pulmonary embolism (PE), characterized by fibro-thrombotic material obliterating large pulmonary arteries. The incidence of CTEPH after PE is about 3%, with patients presenting at advanced stages with compromised haemodynamic profile and limited exercise capacity. Treatment is complex, involving surgery, angioplasty and drugs. There is an urgent need to i) understand why patients develop CTEPH after acute PE and ii) identify and treat patients at risk of post-surgery persistent pulmonary hypertension. Dysfunctional pulmonary arterial endothelial cells (ECs) play a key role in the pathogenesis of CTEPH, by producing factors targeting pulmonary arterial smooth muscle cells (SMCs). Peptidyl-Prolyl Cis/Trans Isomerase NIMA-Interacting protein 1 (Pin1) plays a crucial role in vascular and inflammatory diseases. Its inhibition attenuates tissue factor expression and activity in vascular cells in vitro, and reduces vascular remodelling in vivo. Noteworthy, our preliminary data shows that Pin1 levels are elevated in ECs and plasma from CTEPH patients. We hypothesized that Pin1 is a biomarker for CTEPH and that its inhibition might be beneficial for the prevention of vascular thrombotic diseases such as CTEPH. Therefore, the aims of the proposal are to investigate, using patient cells, tissue, and preclinical animal models whether i) Pin1 is a discriminating biomarker to identify individuals at risk and ii) Pin1 inhibition restores EC dysfunction, and reduce thrombosis in CTEPH. Expected results: Pin1 is a novel biomarker to identify individuals at risk for CTEPH and maybe a novel target in preventing CTEPH.