Kvandova Miroslava, Zemancikova Anna, Berenyiova Andrea, Waczulikova Iveta, Magyarova Silvia, Micurova Andrea, Torok Jozef, Grman Marian, Tomasova Lenka, Misak Anton, Vysoka Zuzana, Manikova Martina, Zvarik Milan, Mydla Patrick, Vlkovicova Jana, Balis Peter, Puzserova Angelika
Institute of Normal and Pathological Physiology, Centre of Experimental Medicine, Slovak Academy of Sciences, Dúbravská cesta 9, 841 04 Bratislava, Slovakia.
Institute of Pathophysiology, Faculty of Medicine, Comenius University Bratislava, Sasinkova 4, 811 08 Bratislava, Slovakia.
Antioxidants (Basel). 2025 Jul 9;14(7):843. doi: 10.3390/antiox14070843.
Metabolic syndrome (MetS) increases the risk of cardiovascular disease development, with sex differences playing a significant role. AMP-activated protein kinase (AMPK), a key regulator of cellular energy homeostasis, becomes dysregulated in MetS, making it a potential therapeutic target. Therefore, we aimed to investigate the role of AMPK in the development of cardiovascular comorbidities in male and female rats with MetS. MetS was induced in young Wistar-Kyoto (WKY) rats through a high-fat diet (HFD; 10 weeks), and the function of AMPK was studied using Compound C (Cmpd C; 1.5 mg/kg, twice per week, during the last 4 weeks). An HFD induced MetS in males, but, in females, it did not affect body weight, blood pressure, or glycemia until AMPK inhibition occurred. Endothelial dysfunction, oxidative stress, and inflammation developed in both HFD male groups, while, in females, these arose only with AMPK inhibition. In both sexes, α1-AMPK activation decreased with eNOS and Nrf2 protein levels after HFD + Cmpd C treatment. Estradiol levels significantly dropped in HFD and Cmpd C females, whereas testosterone levels remained unchanged. Our results suggest that MetS and related cardiovascular comorbidities in males are driven by oxidative stress, inflammation, and endothelial dysfunction, with minimal additive effect of AMPK. In females, MetS arose only when inhibition of AMPK impaired estrogen signalling, emphasising their protective roles. Targeting AMPK-estrogen pathways may provide a therapeutic strategy, particularly for high-risk cardiovascular females and menopausal women.
代谢综合征（MetS）会增加心血管疾病发生的风险，其中性别差异起着重要作用。AMP激活的蛋白激酶（AMPK）是细胞能量稳态的关键调节因子，在MetS中会失调，使其成为一个潜在的治疗靶点。因此，我们旨在研究AMPK在患有MetS的雄性和雌性大鼠心血管合并症发展中的作用。通过高脂饮食（HFD；10周）在年轻的Wistar-Kyoto（WKY）大鼠中诱导MetS，并在最后4周使用化合物C（Cmpd C；1.5mg/kg，每周两次）研究AMPK的功能。高脂饮食在雄性大鼠中诱导了MetS，但在雌性大鼠中，直到发生AMPK抑制之前，它对体重、血压或血糖都没有影响。在两个高脂饮食雄性组中都出现了内皮功能障碍、氧化应激和炎症，而在雌性大鼠中，这些仅在AMPK抑制时出现。在两性中，高脂饮食+化合物C处理后，α1-AMPK激活随eNOS和Nrf2蛋白水平下降。高脂饮食和化合物C处理的雌性大鼠中雌二醇水平显著下降，而睾酮水平保持不变。我们的结果表明，雄性大鼠中的MetS和相关心血管合并症是由氧化应激、炎症和内皮功能障碍驱动的，AMPK的附加作用最小。在雌性大鼠中，只有当AMPK抑制损害雌激素信号时才会出现MetS，这突出了雌激素的保护作用。靶向AMPK-雌激素途径可能提供一种治疗策略，特别是对于高危心血管疾病女性和绝经后女性。
