PDF(Pubmed)
Abstract：
Diabetes accelerates vascular senescence, which is the basis for atherosclerosis and stiffness. The activation of NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome and oxidative stress are closely associated with the deteriorative senescence in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs). For decades, Sodium Tanshinone IIA Sulfonate (STS) has been utilized as a cardiovascular medicine with acknowledged anti-inflammatory and anti-oxidative properties. Nevertheless, the impact of STS on vascular senescence remains unexplored in diabetes. Diabetic mice, primary ECs and VSMCs were transfected with the NLRP3 overexpression/knockout plasmid, the tumor necrosis factor alpha-induced protein 3 (TNFAIP3/A20) overexpression/knockout plasmid, and treated with STS to detect senescence-associated markers. In diabetic mice, STS treatment maintained catalase (CAT) level and vascular relaxation, reduced hydrogen peroxide probe (ROSgreen) fluorescence, p21 immunofluorescence, Senescence β-Galactosidase Staining (SA-β-gal) staining area, and collagen deposition in aortas. Mechanistically, STS inhibited NLRP3 phosphorylation (serine 194), NLRP3 dimer formation, NLRP3 expression, and NLRP3-PYCARD (ASC) colocalization. It also suppressed the phosphorylation of IkappaB alpha (IκBα) and NFκB, preserved A20 and CAT levels, reduced ROSgreen density, and decreased the expression of p21 and SA-β-gal staining in ECs and VSMCs under HG culture. Our findings indicate that STS mitigates vascular senescence by modulating the A20-NFκB-NLRP3 inflammasome-CAT pathway in hyperglycemia conditions, offering novel insights into NLRP3 inflammasome activation and ECs and VSMCs senescence under HG culture. This study highlights the potential mechanism of STS in alleviating senescence in diabetic blood vessels, and provides essential evidence for its future clinical application.
摘要：
糖尿病加速血管衰老,这是动脉粥样硬化和僵硬的基础。NOD样受体家族pyrin结构域含3(NLRP3)炎性小体的激活和氧化应激与内皮细胞(ECs)和血管平滑肌细胞(VSMCs)衰老的恶化密切相关。几十年来,丹参酮IIA磺酸钠（STS）已被用作具有公认的抗炎和抗氧化特性的心血管药物。然而，STS对血管衰老的影响在糖尿病中仍未被研究。糖尿病小鼠,用NLRP3过表达/敲除质粒转染原代EC和VSMC，肿瘤坏死因子α诱导蛋白3（TNFAIP3/A20）过表达/敲除质粒，并用STS处理以检测衰老相关标记。在糖尿病小鼠中，STS治疗维持过氧化氢酶（CAT）水平和血管舒张，还原过氧化氢探针(ROSgreen)荧光,p21免疫荧光，衰老β-半乳糖苷酶染色(SA-β-gal)染色区,和胶原沉积在主动脉中.机械上,STS抑制NLRP3磷酸化（丝氨酸194），NLRP3二聚体形成,NLRP3表达，和NLRP3-PYCARD(ASC)共定位。它还抑制了IkappaBα（IκBα）和NFκB的磷酸化，保存的A20和CAT水平，降低ROSgreen密度，并降低了HG培养下ECs和VSMCs中p21和SA-β-gal染色的表达。我们的发现表明，STS通过调节A20-NFκB-NLRP3炎性体-CAT通路在高血糖条件下减轻血管衰老，为HG培养下NLRP3炎性体激活、EC和VSMC衰老提供了新的见解。这项研究强调了STS在减轻糖尿病血管衰老中的潜在机制。为其未来的临床应用提供了必要的证据。
