Cardiac hypertrophy is the underlying cause of heart failure and is characterized by excessive oxidative stress leading to collagen deposition. Therefore, understanding the signalling mechanisms involved in excessive extracellular matrix deposition is necessary to prevent cardiac remodelling and heart failure. In this study, we hypothesized that hesperetin, a flavanone that elicits the activation of Nrf2 signalling and thereby suppresses oxidative stress, mediated pathological cardiac hypertrophy progression. A cardiac hypertrophy model was established with subcutaneous injection of isoproterenol in male Wistar rats. Oxidative stress markers, antioxidant defense status, and its upstream signalling molecules were evaluated to discover the impacts of hesperetin in ameliorating cardiac hypertrophy. Our results implicate that hesperetin pretreatment resulted in the mitigation of oxidative stress by upregulating antioxidant capacity of the heart. This curative effect might be owing to the activation of the master regulator of antioxidant defense system, known as Nrf2. Further, analysis of Nrf2 revealed that hesperetin enhances its nuclear translocation as well as the expression of its downstream targets (GCLC, NQO1, and HO-1) to boost the antioxidative status of the cells. To support this notion, in vitro studies were carried out in isoproterenol-treated H9c2 cells. Immunocytochemical analysis showed augmented nuclear localization of Nrf2 implicating the action of hesperetin at the molecular level to maintain the cellular redox homeostasis. Thus, it is conceivable that hesperetin could be a potential therapeutic candidate that enhances Nrf2 signalling and thereby ameliorates pathological cardiac remodelling.

中文翻译：

---

针对Nrf2 / ARE信号通路减轻异丙肾上腺素诱导的心肌肥大：橙皮素在氧化还原稳态中的合理作用。

心脏肥大是心力衰竭的根本原因，其特征在于过度的氧化应激导致胶原蛋白沉积。因此，必须了解参与过多细胞外基质沉积的信号传导机制，以防止心脏重塑和心力衰竭。在这项研究中，我们假设橙皮素是一种黄烷酮，能引起Nrf2信号的激活，从而抑制氧化应激，介导病理性心脏肥大的进展。在雄性Wistar大鼠中皮下注射异丙肾上腺素建立了心脏肥大模型。对氧化应激标记，抗氧化防御状态及其上游信号分子进行了评估，以发现橙皮素在改善心脏肥大中的作用。我们的结果表明，橙皮素预处理可通过上调心脏的抗氧化能力来减轻氧化应激。这种治疗效果可能是由于抗氧化剂防御系统的主调节剂Nrf2的激活所致。此外，对Nrf2的分析显示橙皮素增强了其核转运以及下游靶标（GCLC，NQO1和HO-1）的表达，从而增强了细胞的抗氧化状态。为了支持这个概念，Nrf2的分析显示橙皮素增强了其核转运以及下游靶标（GCLC，NQO1和HO-1）的表达，从而增强了细胞的抗氧化状态。为了支持这个概念，Nrf2的分析显示橙皮素增强了其核转运以及下游靶标（GCLC，NQO1和HO-1）的表达，从而增强了细胞的抗氧化状态。为了支持这个概念，在异丙肾上腺素处理的H9c2细胞中进行了体外研究。免疫细胞化学分析显示，Nrf2的核定位增加，暗示橙皮素在分子水平上可维持细胞氧化还原稳态。因此，可以想象橙皮素可能是增强Nrf2信号传导从而改善病理性心脏重塑的潜在治疗候选物。