Perivascular adipose tissue in the pathogenesis of lupus vasculopathy - PROJECT SUMMARY Patients with systemic lupus erythematosus (SLE, commonly called lupus) are at high risk for cardiovascular disease (CVD), a leading cause of death in lupus patients. Perivascular adipose tissue (PVAT) abuts the blood vessels and can play a protective or pathogenic role in vascular disease. Interestingly, lupus patients have a higher amount and density (a marker of inflammation) of PVAT surrounding the thoracic aorta as compared to healthy control subjects. However, the biology of PVAT, and its role in regulating vascular disease in lupus, have not been investigated. Using a lupus-prone mouse model, we demonstrate for the first time that active lupus promotes dysfunctional, inflamed thoracic PVAT, as evidenced by increased immune cell infiltration, reduced expression of adipogenic differentiation markers, adventitial hyperplasia, and a conversion from a brown-like (protective) to a white-like (pathogenic) phenotype in the thoracic aorta. Dysfunctional PVAT, in turn, impairs endothelium-dependent relaxation of the thoracic aorta of murine lupus. Moreover, we demonstrate that PVAT from lupus mice directly impaired endothelial function and promoted wire-induced neointima formation locally when transplanted to wild-type mice. These intriguing data suggest that PVAT acts as a critical driver of lupus- associated vascular disease. Mechanistically, single-nucleus RNA-sequencing (snRNA-seq) and flow cytometry studies showed that active lupus dynamically modified the composition of PVAT by decreasing brown adipocytes and markedly increasing T cells, the most dominant of which were CD8+ T cells producing the proinflammatory cytokine interferon gamma (IFNγ), implying a potential role in dysfunctional PVAT in murine lupus. In this proposal, we will test the following hypotheses: 1) Active lupus promotes phenotypic switching of perivascular adipocytes into a trans-differentiated, proinflammatory phenotype; 2) IFNγ producing CD8+ T cells inhibit adipogenic differentiation and promote PVAT inflammation in lupus; 3) pharmacologically targeting IFNγ improves endothelial function and neointima formation in murine lupus. These studies will lead to better understanding of the mechanistic role of dysfunctional PVAT in lupus and provide novel insights into, and potential therapeutic interventions for, CVD in the context of lupus, which will also shape the focus of my future independent lab. Hong Shi, MD, an assistant professor at Augusta University, will conduct this project as part of 5-year career development plan, dedicating 75% of her time to research, while her clinical effort will be focused on caring for lupus patients. Dr. Shi is mentored by Dr. Neal Weintraub (expert in CVD and PVAT) and Dr. Michelle Kahlenberg (expert in lupus and immunology), with assistance from an extended team, including Drs. Brian Annex and Laura Carbone. Dr. Shi will receive rigorous training in research methods relevant to the Aims while advancing her knowledge in immunology, adipose biology, bioinformatics, and grantsmanship. By completing the defined short- and long-term goals, Dr. Shi will establish her own research laboratory and obtain R01 funding as an independent investigator in lupus-associated CVD.
