Chronic Endurance Exercise Impairs Cardiac Structure and Function in Middle-Aged Mice with Impaired Nrf2 Signaling.
Chronic Endurance Exercise Impairs Cardiac Structure and Function in Middle-Aged Mice with Impaired Nrf2 Signaling.
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DOI：
10.3389/fphys.2017.00268
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发表时间：
2017
影响因子：
4
通讯作者：
Rajasekaran NS
中科院分区：
文献类型：
--
作者：
Shanmugam G;Narasimhan M;Conley RL;Sairam T;Kumar A;Mason RP;Sankaran R;Hoidal JR;Rajasekaran NS
核因子红细胞2相关因子2（Nrf 2）信号传导维持氧化还原稳态，并且其活化显示抑制心脏适应不良。早期，我们报道了急性耐力运动（2天）诱发抗氧化剂细胞保护在年轻的野生型动物，但在老年野生型动物。然而，在以心肌中Nrf 2信号传导和病理性衰老（明显的氧化易感性-Nrf 2缺失）的固有恶化为特征的生物老化（WT）期间重复耐力运动的影响仍然难以捉摸。因此，我们研究的目的是确定慢性耐力运动诱导的心脏适应性老年小鼠与Nrf 2。将WT和Nrf 2-null小鼠（Nrf 2-/-）（>22个月）进行6周的慢性耐力运动（25米/分钟，12%等级）。心肌氧化还原状态通过抗氧化防御基因和蛋白质的表达沿着DMPO-自由基加合物、GSH-NEM和总泛素化的免疫化学检测来评估。通过超声心动图和心电图评估心功能。在安静状态下，Nrf 2的缺失导致抗氧化基因（Nqo 1，Ho 1，Gclm，Cat和Gst-α）表达显著下调，GSH-NEM免疫荧光信号减少。而Nrf 2 −/−小鼠经CEE处理后，Gclc、Nqo 1、Gsr和Gst-α的转录水平与WT同窝小鼠相比出现相似或更显著的降低。此外，CEE上Nrf 2 −/−的心脏显示出特定抗氧化蛋白、G6 PD和CAT沿着GSH减少、DMPO加合物和总泛素化水平显著增加。此外，与WT小鼠相比，CEE导致Nrf 2 −/−心脏中肥大基因（Anf、Bnf和β-Mhc）显著上调（p < 0.05）。此外，与年龄匹配的WT同窝小鼠相比，老年Nrf 2 −/−小鼠表现出更高程度的心脏重塑，与CEE时缩短分数显著降低、ST段显著缩短和J波升高相关。总之，我们的研究结果表明，虽然老年WT和Nrf 2基因敲除动物在CEE后都表现出肥大，但老年Nrf 2基因敲除动物表现出心室重塑，伴有严重的心脏功能异常和舒张功能障碍。
Nuclear factor erythroid 2 related factor 2 (Nrf2) signaling maintains the redox homeostasis and its activation is shown to suppress cardiac maladaptation. Earlier we reported that acute endurance exercise (2 days) evoked antioxidant cytoprotection in young WT animals but not in aged WT animals. However, the effect of repeated endurance exercise during biologic aging (WT) characterized by an inherent deterioration in Nrf2 signaling and pathological aging (pronounced oxidative susceptibility—Nrf2 absence) in the myocardium remains elusive. Thus, the purpose of our study was to determine the effect of chronic endurance exercise-induced cardiac adaptation in aged mice with and without Nrf2. Age-matched WT and Nrf2-null mice (Nrf2−/−) (>22 months) were subjected to 6 weeks chronic endurance exercise (25 meter/min, 12% grade). The myocardial redox status was assessed by expression of antioxidant defense genes and proteins along with immunochemical detection of DMPO-radical adduct, GSH-NEM, and total ubiquitination. Cardiac functions were assessed by echocardiography and electrocardiogram. At sedentary state, loss of Nrf2 resulted in significant downregulation of antioxidant gene expression (Nqo1, Ho1, Gclm, Cat, and Gst-α) with decreased GSH-NEM immuno-fluorescence signals. While Nrf2−/− mice subjected to CEE showed an either similar or more pronounced reduction in the transcript levels of Gclc, Nqo1, Gsr, and Gst-α in relation to WT littermates. In addition, the hearts of Nrf2−/− on CEE showed a substantial reduction in specific antioxidant proteins, G6PD and CAT along with decreased GSH, a pronounced increase in DMPO-adduct and the total ubiquitination levels. Further, CEE resulted in a significant upregulation of hypertrophy genes (Anf, Bnf, and β-Mhc) (p < 0.05) in the Nrf2−/− hearts in relation to WT mice. Moreover, the aged Nrf2−/− mice exhibited a higher degree of cardiac remodeling in association with a significant decrease in fractional shortening, pronounced ST segment, and J wave elevation upon CEE compared to age-matched WT littermates. In conclusion, our findings indicate that while the aged WT and Nrf2 knockout animals both exhibit hypertrophy after CEE, the older Nrf2 knockouts showed ventricular remodeling coupled with profound cardiac functional abnormalities and diastolic dysfunction.