Diabetes Exacerbates Atherosclerosis via Inflammasome- and APOC3-Dependent Pathways

Abstract

Individuals with diabetes suffer from increased cardiovascular disease (CVD) death regardless of statin treatment. The persistently elevated CVD risk among individuals with diabetes suggests the presence of diabetes-associated CVD risks beyond LDL-cholesterol. Multiple risk factors, including glucose, inflammation, and abnormal metabolism of triglyceride-rich lipoproteins (TRLs) and their remnants, have been proposed as contributors to diabetes-associated CVD risk. This work focuses on testing whether increased circulating apolipoprotein C3 (APOC3), inflammasome activation in immune cells, and abnormal TRL metabolism contribute to diabetes-associated atherosclerosis. We have shown that blocking hematopoietic inflammasome activation leads to suppressed atherogenesis in diabetic mice. Our findings further highlight the unique role of hematopoietic inflammasome activation in inducing atherosclerotic lesions but not necrotic core progression in diabetes. Lesion necrotic core progression in diabetes could be dependent on the lesional accumulation of APOC3. Large lesion necrotic cores can lead to CVD events. Previous studies demonstrated that elevated serum APOC3 levels predict incident CVD in humans and promote necrotic core progression in a mouse model of type 1 diabetes, but the underlying APOC3-associated mechanism remains elusive. We showed that delipidated, but not lipidated, APOC3 can induce inflammasome activation. Given the association between lesional APOC3 accumulation and necrotic core progression, we propose that lesional APOC3 and TRL accumulation could be responsible for necrotic core expansion in diabetes. Together, our work demonstrates that diabetes exacerbates atherosclerosis via inflammasome- and APOC3-dependent pathways. These findings suggest that inhibiting both pathways may provide novel therapeutics for reducing CVD risk in individuals with diabetes.