Methylated SNHG3 lncRNA counteracts PSMD4-inhibited angiogenesis by HnRNPA2B1 SUMOylation in peripheral arterial disease.

Peripheral arterial disease (PAD) induced by atherosclerosis causes significant health complications and can lead to amputation. Stimulating angiogenesis is a promising therapeutic strategy to treat patients with PAD, but the precise mechanism governing this process in PAD remains unclear. This study aims to uncover the mechanism governing angiogenesis in PAD. We established in vitro and in vivo models of PAD by culturing human umbilical vein endothelial cells (HUVECs) under hypoxic conditions plus serum starvation and femoral artery dissection in mice, respectively. Targeted long non-coding RNA (lncRNA) small nucleolar RNA host gene 3 (SNHG3) methylation was performed by PspCas13b. Our findings indicate that SNHG3 lncRNA in vascular endothelial cells facilitates angiogenesis by inhibiting proteasome 26S subunit ubiquitin receptor, non-ATPase 4 (PSMD4) in PAD in vitro and in vivo. Mechanistically, methylation increases SNHG3 lncRNA levels by improving its stability. Moreover, methylated SNHG3 lncRNA reduces PSMD4 mRNA by decreasing its stability via heterogeneous nuclear ribonucleoprotein A2/B1 (HnRNPA2B1). Furthermore, ubiquitin-conjugating enzyme E2 I (UBE2I)-mediated SUMOylation of HnRNPA2B1 exacerbates PSMD4 mRNA instability by facilitating HnRNPA2B1- PSMD4 mRNA interaction. Additionally, PSMD4 promotes UBE2I degradation to suppress HnRNPA2B1 SUMOylation, suggesting a negative feedback regulatory loop between PSMD4 and HnRNPA2B1. These findings indicate that methylated SNHG3 lncRNA ameliorates PSMD4-inhibited angiogenesis by interactions with SUMOylated HnRNPA2B1 in PAD.