Abstract 17409: Therapeutic Inhibition of RIP1 Improves Metabolic Dysfunction and Inhibits Atherosclerosis in Mouse Models of Cardiometabolic Diseases

Introduction: Chronic activation of the innate immune system drives inflammation and contributes directly to obesity, insulin resistance and atherosclerosis. Previously we showed that necroptosis, a pro-inflammatory form of programmed cell death, is activated in the vessel wall and drives atherosclerosis via activation of RIP3 and MLKL. We sought to determine upstream regulators of necroptosis in atherosclerosis and metabolic disease, and hypothesized that RIP1, a key regulatory kinase upstream of NFkB activation, apoptosis and necroptosis, drives macrophage inflammation in cardiometabolic diseases. Methods: RIP1 anti-sense oligonucleotides (ASOs, 2 unique sequences) were used to reduce RIP1 expression in 2 mouse models: i) atherosclerotic model [ApoE-/- mice fed a western diet for 8wks] and ii) diet-induced obesity (DIO) model [C57Bl/6 male mice fed a high fat diet for 24 wks]. Mice were given weekly injections of RIP1 ASOs (50 or 100mg/kg) or control ASO (non-targeting). Results: RIP1 ASO treated ApoE-/...