Akbulut Müge, Keskin Aktan Arzu, Sonugür Gizem, Özen Akarca Saadet, Bahar Aslı Nur, Kavak Hatice, Akbulut Gonca
Department of Cardiology, Ankara University Faculty of Medicine, Ankara, Türkiye.
Department of Physiology, Afyon Kocatepe University Faculty of Medicine, Afyon, Türkiye.
Anatol J Cardiol. 2025 Jan 31;29(4):173-80. doi: 10.14744/AnatolJCardiol.2025.4770.
A primary factor in the pathogenesis of aging is oxidative stress, with cardiac inflammation and fibrosis being contributed to by increased oxidative stress as organisms age. Oxidative stress enhances the cardiac fibrotic signaling pathway, with reactive oxygen species inducing cardiac fibrosis through increased expression of the profibrotic factor transforming growth factor-beta 1 (TGF-β1). Furthermore, Wnt/β-catenin signaling pathway is implicated in interstitial fibrosis, which is associated with TGF-β. Sirtuin 2 (SIRT2) is expressed in heart tissue, with protective effects in pathological cardiac hypertrophy. We aimed to investigate the mechanisms of cardiac fibrosis in D-Galactose (D-Gal)-induced accelerated aging, focusing on TGF-β1, β-catenin, and SIRT2.
A total of 30 young male Sprague-Dawley rats were randomly divided into 4 groups: control group, D-Gal group, D-Gal + 4% dimethyl sulfoxide (DMSO) group, and D-Gal + the SIRT2 inhibitor (AGK2) group. After 10 weeks, the rats were sacrificed, and their hearts were removed. SIRT2 expression levels were measured by western blot and gene expression levels of TGF-β1 and β-catenin by quantitative real-time polymerase chain reaction.
Transforming growth factor-beta 1 (TGF-β1) mRNA expression in heart tissue was higher in the D-Gal group compared to all other groups. β-catenin mRNA expression was higher in the D-Gal group than in the D-Gal + AGK2 group. SIRT2 protein expression was higher in the D-Gal + DMSO group compared to the control group. Sirtuin 2 expression was lower in the D-Gal + AGK2 group compared to the D-Gal and D-Gal + DMSO groups.
Sirtuin 2 inhibition attenuates fibrosis, as evidenced by the downregulation of TGF-β1 and β-catenin. Thus, targeting SIRT2 may represent a potential therapeutic strategy for diseases characterized by cardiac fibrosis in the future.
衰老发病机制的一个主要因素是氧化应激，随着生物体衰老，氧化应激增加会导致心脏炎症和纤维化。氧化应激增强心脏纤维化信号通路，活性氧通过增加促纤维化因子转化生长因子-β1（TGF-β1）的表达诱导心脏纤维化。此外，Wnt/β-连环蛋白信号通路与间质纤维化有关，而间质纤维化与TGF-β相关。沉默调节蛋白2（SIRT2）在心脏组织中表达，对病理性心脏肥大具有保护作用。我们旨在研究D-半乳糖（D-Gal）诱导的加速衰老中心脏纤维化的机制，重点关注TGF-β1、β-连环蛋白和SIRT2。
将30只年轻雄性Sprague-Dawley大鼠随机分为4组：对照组、D-Gal组、D-Gal + 4%二甲基亚砜（DMSO）组和D-Gal + SIRT2抑制剂（AGK2）组。10周后，处死大鼠并取出心脏。通过蛋白质免疫印迹法测量SIRT2表达水平，通过定量实时聚合酶链反应测量TGF-β1和β-连环蛋白的基因表达水平。
与所有其他组相比，D-Gal组心脏组织中转化生长因子-β1（TGF-β1）mRNA表达更高。D-Gal组中β-连环蛋白mRNA表达高于D-Gal + AGK2组。与对照组相比，D-Gal + DMSO组中沉默调节蛋白2（SIRT2）蛋白表达更高。与D-Gal组和D-Gal + DMSO组相比，D-Gal + AGK2组中沉默调节蛋白2表达更低。
沉默调节蛋白2抑制可减轻纤维化，TGF-β1和β-连环蛋白的下调证明了这一点。因此，靶向SIRT2可能代表未来针对以心脏纤维化为特征的疾病的潜在治疗策略。
