Long noncoding RNA SNHG1 alleviates high glucose-induced vascular smooth muscle cells calcification/senescence by post-transcriptionally regulating Bhlhe40 and autophagy via Atg10

Abstract

Long noncoding RNAs (lncRNAs) are emerging regulators of vascular diseases, yet their role in diabetic vascular calcification/aging remains poorly understood. In this study, we identified a down-expressed lncRNA SNHG1 in high glucose (HG)-induced vascular smooth muscle cells (HA-VSMCs), which induced excessive autophagy and promoted HA-VSMCs calcification/senescence. Overexpression of SNHG1 alleviated HG-induced HA-VSMCs calcification/senescence. The molecular mechanisms of SNHG1 in HA-VSMCs calcification/senescence were explored by RNA pull-down, RNA immunoprecipitation, RNA stability assay, luciferase reporter assay, immunoprecipitation and Western blot assays. In one mechanism, SNHG1 directly interacted with Bhlhe40 mRNA 3′-untranslated region and increased Bhlhe40 mRNA stability and expression. In another mechanism, SNHG1 enhanced Bhlhe40 protein SUMOylation by serving as a scaffold to facilitate the binding of SUMO E3 ligase PIAS3 and Bhlhe40 protein, resulting in increased nuclear translocation of Bhlhe40 protein. Moreover, Bhlhe40 suppressed the expression of Atg10, which is involved in the process of autophagosome formation. Collectively, the protective effect of SNHG1 on HG-induced HA-VSMCs calcification/senescence is accomplished by stabilizing Bhlhe40 mRNA and promoting the nuclear translocation of Bhlhe40 protein. Our study could provide a novel approach for diabetic vascular calcification/aging.

High serum Bhlhe40 levels are associated with subclinical atherosclerosis in patients with type 2 diabetes mellitus: A cross-sectional study

“…Overexpression of Bhlhe40 exhibited a role in alleviating high glucose-induced VSMCs senescence and calcification. 4,5 This was the first report on the predictive value of serum Bhlhe40 for the prevalence of subclinical atherosclerosis in Chinese adults with T2DM. Unexpectedly, we found that serum Bhlhe40 levels were positively correlated with C-IMT and patients with higher serum Bhlhe40 levels were more prone to subclinical atherosclerosis.…”

“…Overexpression of Bhlhe40 exhibited a role in alleviating high glucose-induced VSMCs senescence and calcification. 4,5…”

“…12 Conversely, our previous studies found a low expression in high glucose-treated VSMCs. 5 The reasons for this discrepancy might be due to the differences in cell types, handling of samples, and study design. Therefore, further studies are urgently needed to explore the mechanism of bhlhe40 in the occurrence and development of atherosclerosis and to verify the relationship between serum Bhlhe40 and cardiovascular disease risk.…”

“…The basic helix-loop-helix transcription factor 40 (Bhlhe40) has been shown to be a key regulator of circadian rhythms, tumorigenesis, and immune response. 3 Our previous studies have found that bhlhe40 was involved in the regulation of high glucose-induced calcification/senescence of vascular smooth muscle cells (VSMCs), 4,5 hinting the involvement of Bhlhe40 in the occurrence and development of atherosclerosis. However, the association between serum Bhlhe40 levels and diabetic macroangiopathy remains unsettled.…”

Regulation of SUMOylation on RNA metabolism in cancers

“…LncRNA ELNAT1 promotes lymphangiogenesis and lymph node (LN) metastasis in bladder cancer (BCa) cell lines by inducing Ubc9 overexpression to catalyze SUMOylation of hnRNPA1 (Chen et al, 2021). LncRNA small nucleolar RNA host gene 1 (SNHG1) enhanced SUMOylation of Bhlhe40 protein by facilitating the binding of SUMO E3 ligase PIAS3 to Bhlhe40, resulting in increased nuclear translocation of Bhlhe40 (Li S et al, 2022). LncRNA SDCBP2-AS1 binds to hnRNP K to repress its SUMOylation, which facilitates the ubiquitination of hnRNP K and β-catenin, thereby promoting the degradation of βcatenin and suppressing tumorigenesis and metastasis in gastric cancer (Han et al, 2022).…”