The influence of Nrf2 on cardiac responses to environmental stressors

Abstract

Nrf2 protects the lung from adverse responses to oxidants, including 100% oxygen (hyperoxia) and airborne pollutants like particulate matter (PM) exposure, but the role of Nrf2 on heart rate (HR) and heart rate variability (HRV) responses is not known. We hypothesized that genetic disruption of Nrf2 would exacerbate murine HR and HRV responses to severe hyperoxia or moderate PM exposures. Nrf2(-/-) and Nrf2(+/+) mice were instrumented for continuous ECG recording to calculate HR and HRV (low frequency (LF), high frequency (HF), and total power (TP)). Mice were then either exposed to hyperoxia for up to 72 hrs or aspirated with ultrafine PM (UF-PM). Compared to respective controls, UF-PM induced significantly greater effects on HR (P < 0.001) and HF HRV (P < 0.001) in Nrf2(-/-) mice compared to Nrf2(+/+) mice. Nrf2(-/-) mice tolerated hyperoxia significantly less than Nrf2(+/+) mice (~22 hrs; P < 0.001). Reductions in HR, LF, HF, and TP HRV were also significantly greater in Nrf2(-/-) compared to Nrf2(+/+) mice (P < 0.01). Results demonstrate that Nrf2 deletion increases susceptibility to change in HR and HRV responses to environmental stressors and suggest potential therapeutic strategies to prevent cardiovascular alterations.

Figure 1

(a) Heart rate (HR, bpm) responses in Nrf2^−/− and Nrf2^+/+ mice following aspiration of either ultrafine particulate matter (UF-PM, <0.1 μm) in saline or saline alone. Significant overall effects between treatment and genotype were found (P < 0.05; Table 1). (b) Low frequency heart rate variability (HRV, ms²/Hz) responses in Nrf2^−/− and Nrf2^+/+ mice following aspiration of either ultrafine particulate matter (UF-PM, <0.1 μm) in saline or saline alone. Significant overall effects between treatments only were found (P < 0.05; Table 1). (c) High frequency (HF) heart rate variability (HRV, ms²/Hz) responses in Nrf2^−/− and Nrf2^+/+ mice following aspiration of either ultrafine particulate matter (UF-PM, <0.1 μm) in saline or saline alone. Significant overall effects between treatment and genotype were found (P < 0.05; Table 1). (d) Low frequency (LF) heart rate variability (HRV, ms²/Hz) responses in Nrf2^−/− and Nrf2^+/+ mice following aspiration of either ultrafine particulate matter (UF-PM, <0.1 μm) in saline or saline alone. Significant overall effects between treatment and genotype were found (P < 0.05; Table 1). Group means ± SEM are presented (n = 4/group).

Figure 2

Time to heart rates of 250 bpm in Nrf2^−/− and Nrf2^+/+ mice during hyperoxia (100% oxygen) exposure. *Significantly different between genotypes (P < 0.001). Group means ± SEM are presented (n = 8/group).

Figure 3

(a) Hourly mean heart rate (HR, bpm) responses in Nrf2^−/− and Nrf2^+/+ mice during hyperoxia (100% oxygen) exposure. Heart rates in Nrf2^−/− mice were significantly reduced from baseline from 34 hr until the end of exposure (P < 0.05). Heart rates in Nrf2^+/+ mice were significantly reduced from baseline from 54 hr until the end of exposure (P < 0.05). (b) Hourly mean low frequency (LF) heart rate variability (HRV, (ms²/Hz) responses in Nrf2^−/− and Nrf2^+/+ during hyperoxia (100% oxygen) exposure. LF HRV reduced in Nrf2^−/− versus Nrf2^+/+ after 40 hr of exposure (P < 0.05). LF HRV in Nrf2^+/+ mice did not change significantly (P > 0.05). (c) Hourly mean high frequency (HF) heart rate variability (HRV, ms²/Hz) responses in Nrf2^−/− and Nrf2^+/+ during hyperoxia (100% oxygen) exposure. HF HRV reduced significantly in Nrf2^−/− versus Nrf2^+/+ at 35 and 36 hrs of exposure (P < 0.05). (d) Hourly mean total power heart rate variability (TP HRV, ms²/Hz) responses in Nrf2^−/− and Nrf2^+/+ during hyperoxia (100% oxygen) exposure. TP HRV reduced in Nrf2^−/− versus Nrf2^+/+ after 43 hr to the end of the exposure (P < 0.05). Group means ± SEM are presented (n = 8/group).