Targeting chondroitin synthase 1 attenuates hyperplastic arterial remodeling via gene therapy

Chondroitin sulfate glycosaminoglycans accumulate excessively in the extracellular matrix during pathological remodeling and exacerbate cardiovascular deterioration. Here we show that chondroitin synthase 1 (CHSY1) is the primary enzyme responsible for chondroitin sulfate synthesis, as identified through in-house single-cell RNA sequencing. Chsy1 knockout mice display markedly reduced chondroitin sulfate levels and are protected against arterial remodeling and fibrosis in two independent disease models, with hyperplasia and inflammation completely abolished in both coronary and carotid arteries. In vitro, CHSY1 inhibition regulates multiple cellular processes such as activation and migration of macrophages, fibroblast-to-myofibroblast transition, and hyperproliferation of vascular smooth muscle cells. Cross-referencing transcriptome and proteome analysis reveal that NOTCH3 signaling is associated with CHSY1 modulation. Importantly, in vivo Chsy1 knockdown by RNA interference after disease onset significantly preserves structural integrity and maintains cardiovascular functions. In conclusion, inhibiting CHSY1 is both safe and effective in interfering with CS over-synthesis and preventing vasculopathy, representing a potent therapeutic target for a broad spectrum of diseases driven by hyperplastic arterial remodeling.