Endovascular Health and Platelet Activity in Psoriasis

PROJECT SUMMARY/ABSTRACT Background: Psoriasis is a common chronic inflammatory skin disease associated with an ~50% increased risk of cardiovascular disease (CVD) compared to matched controls. The influence of psoriasis-related systemic inflammation on vascular health and subsequent cardiovascular (CV) risk is not fully known. Vascular endothelial dysfunction, activated platelets, and the interaction between the two are instrumental to the pathogenesis of atherosclerosis. As a way to understand mechanisms of increased CV risk in psoriasis, this study will test the overarching hypothesis that the vascular endothelium in psoriasis is inflamed, dysfunctional, and contributes to CVD development as assessed by endovascular and platelet phenotyping, and that platelets from patients with psoriasis act as effector cells promoting impaired vascular health. To develop therapeutic targets to reduce CV risk, mechanism(s) that lead to the development of clinical CVD must be clarified. Preliminary Data: Our group has shown using direct brachial vein endothelial cell analysis, that patients with psoriasis exhibit impaired vascular endothelial health. Furthermore, unbiased analysis highlights inflammasome (IL-1β) signaling with downstream IL-6 protein production as the highest differentially expressed systemic pathway in psoriasis and correlated with impaired endothelial vascular health. Our preliminary data also reveal that patients with psoriasis overexpress P-selectin (a marker of platelet activation), directly activate cultured human aortic endothelial cells in vitro, and that markers of platelet activation correlate with serum IL-6 levels. This suggests that platelets contribute to the impaired vascular health we observe in psoriasis. These findings have clinical implications because randomized clinical trials targeting the inflammasome pathway (with a corresponding circulating IL-6 reduction) in patients with established CVD reduced cardiac events. Methods: We will recruit 100 psoriasis and 50 healthy age-, sex-, race/ethnicity matched controls across the spectrum of psoriatic disease and various treatment modalities to explore: (1) Vascular health in vivo by flow- mediated brachial artery reactivity testing and pulse wave velocity studies, and directly ex vivo via analysis of endothelial cells obtained from brachial veins; (2) Platelet biology through investigations into platelet reactivity, platelet aggregation, and the platelets ability to activate endothelial cells in vitro. Objectives and Career Development: No study has shown that targeting psoriatic disease activity reduces the development of CVD. This proposal uses a highly collaborative environment between experts in CV and platelet biology, immunology, dermatology, and rheumatology. It will lay the groundwork to propose future larger-scale studies designed to reduce CV risk in patients with psoriasis. Furthermore, it will allow the PI to become an expert in pro-inflammatory conditions, refine innovative methodologies and laboratory techniques to study mechanisms of subclinical CVD, and provide a framework to become an independent clinical- translational investigator.