Down-regulation of KMT2D mitigates neointimal hyperplasia following carotid artery injury in diabetic rats

Abstract

Neointimal hyperplasia (NIH) is a critical pathological process in diabetic vascular restenosis, yet the role of histone-lysine N-methyltransferase 2D (KMT2D) remains undefined. Using a diabetic rat carotid injury model and high glucose (HG)-stimulated vascular smooth muscle cells (VSMCs) with lentivirus-mediated Kmt2d knockdown, we demonstrate that hyperglycemia significantly upregulates KMT2D expression in vascular tissues and VSMCs. KMT2D suppression attenuated HG-induced VSMC proliferation and migration. Local shKmt2d delivery in diabetic rats reduced injury-induced neointimal hyperplasia, collagen deposition, and expression of proliferative and inflammatory markers. Mechanistically, KMT2D catalyzed H3K4 monomethylation (H3K4me1) to transcriptionally activate the prostaglandin receptor EP3, thereby enhancing Akt phosphorylation at Ser473 and driving VSMC phenotypic switching. Our findings establish the KMT2D-H3K4me1-EP3-Akt signaling axis as a crucial epigenetic regulator of diabetic vascular remodeling. Targeting KMT2D represents a promising dual therapeutic strategy against diabetic vascular complications.