Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Bratislava, Slovakia.
Institute for Heart Research, Centre of Experimental Medicine, Slovak Academy of Sciences, Bratislava, Slovakia.
Front Endocrinol (Lausanne). 2022 Dec 8;13:1029750. doi: 10.3389/fendo.2022.1029750. eCollection 2022.
Quercetin (Que) is a potent anti-inflammatory and antioxidant flavonoid with cardioprotective potential. However, very little is known about the signaling pathways and gene regulatory proteins Que may interfere with, especially in diabetic cardiomyopathy. Therefore, we aimed to study the potential cardioprotective effects of Que on the cardiac phenotype of type 2 diabetes mellitus (T2DM) accompanied by obesity.
For this experiment, we used Zucker Diabetic Fatty rats (fa/fa) and their age-matched lean controls (fa/+) that were treated with either vehicle or 20 mg/kg/day of Que for 6 weeks. Animals underwent echocardiographic (echo) examination before the first administration of Que and after 6 weeks.
After the initial echo examination, the diabetic rats showed increased E/A ratio, a marker of left ventricular (LV) diastolic dysfunction, in comparison to the control group which was selectively reversed by Que. Following the echo analysis, Que reduced LV wall thickness and exhibited an opposite effect on LV luminal area. In support of these results, the total collagen content measured by hydroxyproline assay was decreased in the LVs of diabetic rats treated with Que. The follow-up immunoblot analysis of proteins conveying cardiac remodeling pathways revealed that Que was able to interfere with cardiac pro-hypertrophic signaling. In fact, Que reduced relative protein expression of pro-hypertrophic transcriptional factor MEF2 and its counter-regulator HDAC4 along with pSer-HDAC4. Furthermore, Que showed potency to decrease GATA4 transcription factor, NFAT3 and calcineurin, as well as upstream extracellular signal-regulated kinase Erk5 which orchestrates several pro-hypertrophic pathways.
In summary, we showed for the first time that Que ameliorated pro-hypertrophic signaling on the level of epigenetic regulation and targeted specific upstream pathways which provoked inhibition of pro-hypertrophic signals in ZDF rats. Moreover, Que mitigated T2DM and obesity-induced diastolic dysfunction, therefore, might represent an interesting target for future research on novel cardioprotective agents.
槲皮素（Que）是一种具有强大抗炎和抗氧化作用的类黄酮，具有心脏保护作用。然而，人们对 Que 可能干扰的信号通路和基因调节蛋白知之甚少，尤其是在糖尿病性心肌病中。因此，我们旨在研究 Que 对 2 型糖尿病（T2DM）合并肥胖的心脏表型的潜在保护作用。
在这项实验中，我们使用 Zucker 糖尿病肥胖大鼠（fa/fa）及其年龄匹配的瘦对照（fa/+），这些动物用载体或 20mg/kg/天的 Que 治疗 6 周。动物在第一次给予 Que 之前和 6 周后接受超声心动图（echo）检查。
在最初的 echo 检查后，与对照组相比，糖尿病大鼠的 E/A 比值增加，这是左心室（LV）舒张功能障碍的标志物，而 Que 选择性地逆转了这一比值。在回声分析之后，Que 降低了 LV 壁厚度，并对 LV 内腔面积产生了相反的影响。这些结果得到了支持，羟脯氨酸测定法测量的 LV 总胶原蛋白含量在 Que 治疗的糖尿病大鼠中减少。随后对传递心脏重塑途径的蛋白质进行免疫印迹分析表明，Que 能够干扰心脏的促肥厚信号。事实上，Que 降低了促肥厚转录因子 MEF2 及其拮抗物 HDAC4 的相对蛋白表达，以及 pSer-HDAC4。此外，Que 显示出降低 GATA4 转录因子、NFAT3 和钙调神经磷酸酶以及协调几种促肥厚途径的上游细胞外信号调节激酶 Erk5 的能力。
总之，我们首次表明，Que 改善了 ZDF 大鼠的表观遗传调控水平上的促肥厚信号，并针对引发促肥厚信号抑制的特定上游途径。此外，Que 减轻了 T2DM 和肥胖引起的舒张功能障碍，因此，可能是未来研究新型心脏保护剂的一个有趣目标。
