Elevated mitochondrial superoxide contributes to enhanced chemoreflex in heart failure rabbits

Ding Y, Li Y, Zimmerman MC, Schultz HD. Elevated mitochondrial superoxide contributes to enhanced chemoreflex in heart failure rabbits. Am J Physiol Regul Integr Comp Physiol 298: R303-R311, 2010. First published November 18, 2009; doi:10.1152/ajpregu.00629.2009.-Peripheral chemoreflex sensitivity is enhanced in both clinical and experimental chronic heart failure (CHF). Here we investigated the role of manganese superoxide dismutase (MnSOD), the SOD isoform specially targeted to mitochondria, and mitochondrial superoxide levels in the enhanced chemoreceptor activity and function of the carotid body (CB) in CHF rabbits. CHF suppressed MnSOD protein expression and elevated mitochondrial superoxide levels in CB compared with that in sham CB. Adenovirus (Ad) MnSOD (1 x 10(8) plaque-forming units/ml) gene transfer selectively to the CBs normalized mitochondrial superoxide levels in glomus cells from CHF CB. In addition, Ad MnSOD reduced the elevation of superoxide level in CB tissue from CHF rabbits. Ad MnSOD significantly increased MnSOD expression in CHF CBs and normalized the baseline renal sympathetic nerve activity and the response of renal sympathetic nerve activity to hypoxia in CHF rabbits. Ad MnSOD decreased baseline single-fiber discharge from CB chemoreceptors compared with Ad Empty (6.3 +/- 1.5 vs. 12.7 +/- 1.4 imp/s at similar to 100-Torr PO2, P < 0.05) and in response to hypoxia (20.5 +/- 1.8 vs. 32.6 +/- 1.4 imp/s at similar to 40-Torr PO2, P < 0.05) in CHF rabbits. Compared with Ad Empty, Ad MnSOD reversed the blunted K+ currents in CB glomus cells from CHF rabbits (385 +/- 11 vs. 551 +/- 20 pA/pF at +70 mV, P < 0.05). The results suggest that decreased MnSOD in the CB and elevated mitochondrial superoxide levels contribute to the enhanced CB chemoreceptor activity and peripheral chemoreflex function in CHF rabbits.