ETV5-Mediated Transcriptional Repression of DDIT4 Blocks Macrophage Pro-Inflammatory Activation in Diabetic Atherosclerosis

Atherosclerosis risk is elevated in diabetic patients, but the underlying mechanism such as the involvement of macrophages remains unclear. Here, we investigated the underlying mechanism related to the pro-inflammatory activation of macrophages in the development of diabetic atherosclerosis. Bioinformatics tools were used to analyze the macrophage-related transcriptome differences in patients with atherosclerosis and diabetic mice. LDLR mice with DDIT4 depletion were generated and fed a Western diet to induce atherosclerosis. DDIT4 expression was elevated in diabetic mice and patients with atherosclerosis. Macrophage proinflammatory factors F4/80, Il-6, and TNFα were reduced in DDIT4LDLR mice and necrotic areas were decreased in the aortic root. Atherosclerotic plaque stability was increased in DDIT4LDLR mice, as evidenced by increased collagen and smooth muscle cell content. DDIT4, regulated by ETV5, acted on macrophages, affecting lipid accumulation, migration capacity, and pro-inflammatory responses. Knockdown of ETV5 increased expression of DDIT4 and pro-inflammatory factors in macrophages, increased necrotic core area in the aortic root, and decreased stability of atherosclerotic plaques in mice, which was abated by DDIT4 knockdown. The findings provide new insight into how diabetes promotes atherosclerosis and support a model wherein loss of ETV5 sustains transcription of DDIT4 and the pro-inflammatory activation of macrophages.