Laboratorio de Farmacología Experimental Básica y Traslacional, Área de Farmacología, Departamento de Patología, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Mendoza, Argentina.
Universidad Maimónides, Ciudad Autónoma de Buenos Aires, Argentina.
Curr Hypertens Rep. 2023 Jun;25(6):91-106. doi: 10.1007/s11906-023-01240-w. Epub 2023 Apr 13.
To address the mechanistic pathways focusing on mitochondria dysfunction, oxidative stress, sirtuins imbalance, and other contributors in patient with metabolic syndrome and cardiovascular disease. Sodium glucose co-transporter type 2 (SGLT-2) inhibitors deeply influence these mechanisms. Recent randomized clinical trials have shown impressive results in improving cardiac function and reducing cardiovascular and renal events. These unexpected results generate the need to deepen our understanding of the molecular mechanisms able to generate these effects to help explain such significant clinical outcomes.
Cardiovascular disease is highly prevalent among individuals with metabolic syndrome and diabetes. Furthermore, mitochondrial dysfunction is a principal player in its development and persistence, including the consequent cardiac remodeling and events. Another central protagonist is the renin-angiotensin system; the high angiotensin II (Ang II) activity fuel oxidative stress and local inflammatory responses. Additionally, sirtuins decline plays a pivotal role in the process; they enhance oxidative stress by regulating adaptive responses to the cellular environment and interacting with Ang II in many circumstances, including cardiac and vascular remodeling, inflammation, and fibrosis. Fasting and lower mitochondrial energy generation are conditions that substantially reduce most of the mentioned cardiometabolic syndrome disarrangements. In addition, it increases sirtuins levels, and adenosine monophosphate-activated protein kinase (AMPK) signaling stimulates hypoxia-inducible factor-1β (HIF-1 beta) and favors ketosis. All these effects favor autophagy and mitophagy, clean the cardiac cells with damaged organelles, and reduce oxidative stress and inflammatory response, giving cardiac tissue protection. In this sense, SGLT-2 inhibitors enhance the level of at least four sirtuins, some located in the mitochondria. Moreover, late evidence shows that SLGT-2 inhibitors mimic this protective process, improving mitochondria function, oxidative stress, and inflammation. Considering the previously described protection at the cardiovascular level is necessary to go deeper in the knowledge of the effects of SGLT-2 inhibitors on the mitochondria function. Various of the protective effects these drugs clearly had shown in the trials, and we briefly describe it could depend on sirtuins enhance activity, oxidative stress reduction, inflammatory process attenuation, less interstitial fibrosis, and a consequent better cardiac function. This information could encourage investigating new therapeutic strategies for metabolic syndrome, diabetes, heart and renal failure, and other diseases.
探讨代谢综合征和心血管疾病患者中线粒体功能障碍、氧化应激、沉默调节蛋白失衡及其他因素的作用机制，以及钠-葡萄糖共转运蛋白 2（SGLT-2）抑制剂对这些机制的影响。最近的随机临床试验结果表明，SGLT-2 抑制剂可显著改善心功能，减少心血管和肾脏事件。这些意外结果促使我们深入了解能够产生这些作用的分子机制，以帮助解释如此显著的临床结果。
代谢综合征和糖尿病患者中心血管疾病的患病率很高。此外，线粒体功能障碍是其发生和持续存在的主要因素，包括随后的心脏重构和事件。肾素-血管紧张素系统（RAS）也是一个核心因素；血管紧张素 II（Ang II）活性增加会导致氧化应激和局部炎症反应。此外，沉默调节蛋白的下降在这个过程中起着关键作用；它们通过调节细胞环境的适应性反应，以及在许多情况下与 Ang II 相互作用，增强氧化应激，包括心脏和血管重构、炎症和纤维化。禁食和减少线粒体能量生成会大大减少上述大部分代谢综合征紊乱。此外，它还会增加沉默调节蛋白的水平，激活腺苷酸活化蛋白激酶（AMPK）信号通路，刺激低氧诱导因子-1β（HIF-1β），促进酮体生成。所有这些作用都有利于自噬和线粒体自噬，清除心脏细胞中受损的细胞器，减少氧化应激和炎症反应，为心脏组织提供保护。在这方面，SGLT-2 抑制剂可增强至少四种沉默调节蛋白的水平，其中一些位于线粒体中。此外，最近的证据表明，SGLT-2 抑制剂可模拟这种保护过程，改善线粒体功能、氧化应激和炎症。考虑到之前描述的心血管保护作用，有必要更深入地了解 SGLT-2 抑制剂对线粒体功能的影响。这些药物在试验中表现出的各种保护作用，我们简要描述一下，这些作用可能依赖于沉默调节蛋白活性的增强、氧化应激的减少、炎症过程的减弱、间质纤维化的减少以及随后心脏功能的改善。这些信息可能会鼓励研究代谢综合征、糖尿病、心力衰竭和肾衰竭及其他疾病的新治疗策略。
