Heparanase gene deficiency suppresses atherosclerosis progression and enhances plaque stability in apolipoprotein E gene knockout mice with diabetes

Diabetes mellitus accelerates the development of atherosclerotic cardiovascular disease. Heparanase, the sole enzyme responsible for cleaving heparan sulfates in the endothelial glycocalyx and subendothelial extracellular matrix, plays important pro-inflammatory roles in diabetes and atherosclerosis. However, the role of heparanase in diabetes-accelerated atherosclerosis is unknown. This study investigated the impact of heparanase gene-deficiency on atherosclerosis development in non-diabetic and streptozotocin (STZ)-treated, diabetic apolipoprotein E gene knockout (ApoE-/-) mice fed a normal chow diet for eight weeks. At the study endpoint, atherosclerotic lesion size and stability phenotype, along with blood glucose, serum lipid and pro-inflammatory cytokine profiles were assessed. Compared to non-diabetic control ApoE-/- mice, STZ-treated, diabetic ApoE-/- mice exhibited significant increases in blood glucose, serum lipids, circulating MCP-1 and IL-6 levels, and the development of atherosclerotic lesion burden in the aortic sinus and aorta. While heparanase deficiency did not affect blood glucose or serum lipid levels, it significantly reduced the diabetes-dependent increase in circulating MCP-1 levels and diabetes-accelerated development of atherosclerotic lesions in the aortic sinus and aorta. Analysis of lesion composition and phenotype showed that diabetic ApoE-/- mice commonly exhibited advanced atherosclerotic lesions with well-developed necrotic cores, whereas diabetic heparanase-deficient ApoE-/- mice displayed early-stage atherosclerotic lesions, characterised by significantly smaller necrotic cores and increased collagen and smooth muscle cell (SMC) content. This study demonstrates that heparanase is a prominent pro-inflammatory protein driving the diabetes-accelerated formation of advanced atherosclerotic lesions with an unstable phenotype. Heparanase therefore represents a new therapeutic target for suppressing atherosclerotic cardiovascular disease in people with diabetes.