Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska
Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska.
J Pharmacol Exp Ther. 2019 Dec;371(3):642-651. doi: 10.1124/jpet.119.261792. Epub 2019 Oct 10.
Oxidative stress plays an important role in the pathogenesis of chronic heart failure (CHF) in many tissues. Increasing evidence suggests that systemic activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) signaling can protect against postinfarct cardiac remodeling by reducing oxidative stress. However, it remains to be elucidated if Nrf2 activation exerts therapeutic effects in the CHF state. Here, we investigated the beneficial hemodynamic effects of bardoxolone methyl (2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid methyl ester, CDDO-Me), a pharmacological activator of Nrf2, in a rodent model of CHF. Based on echocardiographic analysis, rats at 12 weeks post-myocardial infarction (MI) were randomly split into four groups. CDDO-Me (5 mg/kg, i.p.) was administered daily for another 2 weeks in sham and CHF rats and compared with vehicle treatment. Echocardiographic and hemodynamic analysis suggest that short-term CDDO-Me administration increased stroke volume and cardiac output in CHF rats and decreased left ventricle end-diastolic pressure. Molecular studies revealed that CDDO-Me-induced cardiac functional improvement was attributed to an increase of both Nrf2 transcription and translation, and a decrease of oxidative stress in the noninfarcted areas of the heart. Furthermore, CDDO-Me reduced NF-B binding and increased Nrf2 binding to the CREB-binding protein, which may contribute to the selective increase of Nrf2 downstream targets, including NADPH Oxidase Quinone 1, Heme Oxygenase 1, Catalase, and Glutamate-Cysteine Ligase Catalytic Subunit, and the attenuation of myocardial inflammation in CHF rats. Our findings suggest that Nrf2 activation may provide beneficial cardiac effects in MI-mediated CHF. SIGNIFICANCE STATEMENT: Chronic heart failure (CHF) is the leading cause of death among the aged worldwide. The imbalance between pro- and antioxidant pathways is a determinant in the pathogenesis of CHF. Systemic activation of Nrf2 and antioxidant protein signaling by bardoxolone methyl may have beneficial effects on cardiac function and result in improvements by enhancing antioxidant enzyme expression and attenuating myocardial inflammation.
氧化应激在许多组织的慢性心力衰竭（CHF）发病机制中起着重要作用。越来越多的证据表明，核因子（红系衍生 2）样 2（Nrf2）信号的系统激活可以通过减少氧化应激来保护梗死后心脏重构。然而，Nrf2 的激活是否在 CHF 状态下发挥治疗作用仍有待阐明。在这里，我们研究了 bardoxolone 甲基（2-氰基-3,12-二氧代齐墩果酸-1,9（11）-二烯-28-酸甲酯，CDDO-Me）作为 Nrf2 药理学激活剂在 CHF 啮齿动物模型中的有益血流动力学效应。基于超声心动图分析，心肌梗死（MI）后 12 周的大鼠被随机分为四组。在假手术和 CHF 大鼠中，每日腹腔注射 CDDO-Me（5mg/kg）持续 2 周，并与载体处理进行比较。超声心动图和血流动力学分析表明，短期 CDDO-Me 给药可增加 CHF 大鼠的每搏量和心输出量，并降低左心室舒张末期压。分子研究表明，CDDO-Me 诱导的心脏功能改善归因于 Nrf2 转录和翻译的增加，以及心脏未梗死区氧化应激的减少。此外，CDDO-Me 降低了 NF-B 结合，并增加了 Nrf2 与 CREB 结合蛋白的结合，这可能有助于 Nrf2 下游靶标的选择性增加，包括 NADPH 氧化酶醌 1、血红素加氧酶 1、过氧化氢酶和谷氨酸-半胱氨酸连接酶催化亚单位，并减轻 CHF 大鼠的心肌炎症。我们的研究结果表明，Nrf2 激活可能为 MI 介导的 CHF 提供有益的心脏效应。意义声明：慢性心力衰竭（CHF）是全球老年人死亡的主要原因。促氧化剂和抗氧化剂途径之间的失衡是 CHF 发病机制的决定因素。Bardoxolone 甲基通过激活 Nrf2 和抗氧化蛋白信号可能对心脏功能有益，并通过增强抗氧化酶表达和减轻心肌炎症来改善。
