血管钙化是老年人和糖尿病个体心血管风险的普遍标志。衰老血管平滑肌细胞(VSMC)参与钙化;然而,相关的潜在机制仍然未知。由胞质DNA引起的干扰素基因1(STING1)的胞质DNA传感接头刺激物的异常激活,特别是从受损的线粒体泄漏出来的,是衰老相关疾病的催化剂。尽管油酰乙醇胺(OEA)是一种内源性生物活性脂质介质,具有脂质超负荷相关的血管保护作用,其在糖尿病血管钙化中的益处仍未表征。这项研究集中于STING1在糖尿病线粒体功能障碍介导的钙化和VMSC过早衰老中的作用以及OEA对这些病理过程的影响。在糖尿病大鼠/小鼠体内主动脉钙化模型和Nε-羧甲基赖氨酸(CML)诱导的体外VSMC钙化模型中,衰老水平,STING1信号激活,和线粒体损伤标记显著增强;然而,这些改变被OEA明显缓解,部分以核因子红系2相关因子2(Nrf2)依赖性方式,在STING1敲除小鼠和STING1敲除VSMC中观察到相似的抗钙化和衰老作用。机械上,线粒体DNA(mtDNA)损伤被CML以活性氧依赖的方式加重,随后是mtDNA泄漏到细胞质中,通过STING1途径激活促进VSMC衰老相关钙化。OEA治疗通过维持Nrf2易位到细胞核而增强细胞抗氧化能力,从而显著减弱上述CML的细胞毒性作用。总的来说,靶向STING1,一种新定义的VSMC衰老调节剂,有助于抗血管钙化作用。
Vascular calcification is a prevalent hallmark of cardiovascular risk in elderly and diabetic individuals. Senescent vascular smooth muscle cells (VSMCs) participate in calcification; however, the associated underlying mechanisms remain unknown. Aberrant activation of the cytosolic DNA sensing adaptor stimulator of interferon gene 1 (
STING1) caused by cytosolic DNA, particularly that leaked from damaged mitochondria, is a catalyst for aging-related diseases. Although oleoylethanolamide (OEA) is an endogenous bioactive lipid mediator with lipid overload-associated vasoprotective effects, its benefit in diabetic vascular calcification remains uncharacterized. This study focused on the role of
STING1 in mitochondrial dysfunction-mediated calcification and premature VMSC senescence in diabetes and the effects of OEA on these pathological processes. In diabetic in vivo rat/mouse aorta calcification models and an in vitro VSMC calcification model induced by Nε-carboxymethyl-lysine (CML), senescence levels,
STING1 signaling activation, and mitochondrial damage markers were significantly augmented; however, these alterations were markedly alleviated by OEA, partially in a nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent manner, and similar anti-calcification and senescence effects were observed in STING1-knockout mice and
STING1-knockdown VSMCs. Mechanistically, mitochondrial DNA (mtDNA) damage was aggravated by CML in a reactive oxygen species-dependent manner, followed by mtDNA leakage into the cytosol, contributing to VSMC senescence-associated calcification via STING1 pathway activation. OEA treatment significantly attenuated the aforementioned cytotoxic effects of CML by enhancing cellular antioxidant capacity through the maintenance of Nrf2 translocation to the nucleus. Collectively, targeting
STING1, a newly defined VSMC senescence regulator, contributes to anti-vascular calcification effects.