Chronic Endurance Exercise Impairs Cardiac Structure and Function in Middle-Aged Mice with Impaired Nrf2 Signaling

Abstract

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.

Real-Ambient Particulate Matter Exposure-Induced Cardiotoxicity in C57/B6 Mice

“…However, in contrary to our expectation, the Nrf2 knockout animals had a mixed response following PM exposure comparing to their wildtype littermates: Nrf2 knockout indeed further deteriorated some of the endpoints, such as the left ventricle mass and diastolic left ventricular volume. Increased left ventricle mass indicated the potential of cardiac hypertrophy, which has commonly been reported following Nrf2 knockout (Shanmugam et al, 2017). On the other hand, the knockout of Nrf2 abolished some of the detrimental changes observed in wildtype exposed animals, such as stroke volume, ejection fraction, fractional shortening, and systolic left ventricular volume.…”

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

“…8). A role of NRF2 in preventing these pathophenotypes has been demonstrated in Nrf2 2/2 mice, which exhibit impaired cardiac structure (more remodeling events) and function (less fractional shortening) in response to chronic endurance exercise (Shanmugam et al, 2017a). They are also more susceptible to develop heart failure after myocardial infarction (Strom and Chen, 2017).…”

Mitochondrial Antioxidant Enzymes and Endurance Exercise-induced Cardioprotection against Ischemia-Reperfusion Injury

“…54 In support of this notion, recent studies have reported that NRF2mediated heme oxygenase-1 (HO-1) upregulation in the heart enhances MnSOD activities via carbon monoxide production upon HO-1 potentiation. 55 Currently, whether this notion is applicable to endurance, exercise-induced cardioprotection remain enigmatic because long-term endurance exercise impairs NRF2 signaling, resulting in cardiac dysfunction, 56 whereas moderate intensity endurance exercise improves cardiac oxidative stress via upregulation of NRF2 expression. 57 Therefore, further mechanistic studies are needed to determine the functional role of NRF2 in MnSOD regulation and involvement in exercise-induced cardioprotection.…”