Abstract 323: Rspo2 Overexpression Attenuates Hepatic Lipid Accumulation And Atherosclerosis

Aims: We have recently reported elevated RSPO2 levels in human and murine atherosclerotic arteries and discovered its anti-lymphangiogenic potential. However, the precise role of RSPO2 in atherosclerosis is not known. In this study, we investigated the effects of RSPO2 overexpression on hepatosteatosis and atherosclerosis development. Methods and Results: Atheroprone ♂ and ♀ Apoe -/- mice were injected with AAV8- GFP or AAV8- Rspo2 , fed a Western diet for 12 weeks, and analyzed for hepatic lipid accumulation and atherosclerotic lesion formation. Our quantitative RT-PCR data revealed increased Rspo2 mRNA expression in the liver, kidney and spleen of AAV8- Rspo2 -injected mice compared with control mice. Oil Red O (ORO) staining showed reduced hepatic lipid deposition in mice injected with AAV8- Rspo2 compared with AAV8- GFP mice. Additionally, there were reduced levels of hepatic triglyceride, non-esterified fatty acid, and lipid peroxidation in Rspo2 -overexpressing mice. Rspo2 overexpression reduced hepatic fibrosis and macrophage accumulation as indicated by reduced expression of SMA and CD68 in liver tissue. Additionally, decreased mRNA expression of proinflammatory and cholesterol metabolism-related genes was found in liver of AAV8- Rspo2 -injected mice. En face ORO staining of aortae and aortic root sections demonstrated suppressed atherosclerosis in mice with Rspo2 overexpression. Interestingly, AAV8- Rspo2 -injected mice had decreased weight gain over the course of Western diet feeding in comparison to control mice, however, no differences in fasting blood glucose and plasma total cholesterol levels were observed between the two groups. Conclusions: Taken together, these findings suggest that global Rspo2 overexpression in hypercholesterolemic mice suppresses hepatic lipid accumulation and reduces atherosclerosis.