Abstract 15852: Inhibition of Calcineurin/NFAT Signaling Limits the Cardioprotective Effects of Exercise by Reducing the Nitrite Reductase Capacity of the Heart
Background: The infarct sparing effects of exercise have been reported following both long-term and short-term training regimens. However, the majority of the studies have demonstrated only a modest reduction in infarct size (∼20%), despite the reported upregulation of endogenous protective signaling molecules. Here we investigated if therapy with nitrite, a stable nitric oxide metabolite shown to afford cytoprotection, could provide additional cardioprotection in the setting of exercise against acute myocardial ischemia-reperfusion (MI/R) injury.
Methods and Results: Mice that engaged in voluntary exercise for 4 wks (VE 4 wks) revealed an 18% reduction in infarct size per area-at-risk (INF/AAR) following 45 min of MI and 24 hr of R when compared to sedentary (SED) mice (49 vs. 60%, p<0.05), whereas mice given nitrite therapy (25 mg/L in drinking water) showed a 53% decrease (28 vs. 60%, p<0.001 vs. SED). However, the combination of VE 4 wks and nitrite (VE+NO2 4 wks) exhibited no further protection than VE alone (49 vs. 60%, p<0.05 vs. SED). Although the VE and nitrite therapy mice showed similar nitrite levels in the heart, cardiac nitrite reductase activity was significantly (p<0.05 vs. SED) reduced in the VE mice, as well as the cardiac gene and protein expression of myoglobin, a known nitrite reductase (p<0.05 vs. SED). Stimulation of the calcineurin/NFAT system transcriptionally activates myoglobin. Additional studies revealed that VE mice exhibited an increase in the nuclear expression of the phosphorylated (inactive) form of NFATc2 and an increase in the calcineurin inhibiting sarcomeric protein calsarcin-1 (p<0.05 vs. SED).
Conclusions: These data suggest that VE downregulates cardiac myoglobin levels by inhibiting calcineurin/NFAT signaling via an upregulation of calsarcin-1. Additionally, these results suggest that the modest infarct sparing effects of VE are the result of a decrease in the hearts ability to reduce nitrite to nitric oxide during MI/R.
- © 2010 by American Heart Association, Inc.