Recovery of cytochrome c oxidase activity is associated with regression of pressure overload hypertrophic cardiomyopathy by copper supplementation in mice

Sustained pressure overload causes cardiac hypertrophy and the transition to heart failure. We show here that dietary supplementation with physiologically relevant levels of copper (Cu) reverses pre‐established hypertrophic cardiomyopathy in the presence of pressure overload induced by ascending aortic constriction (AAC) in mouse model. We subjected adult male mice (10 wks old) to AAC. Mice were fed standard AIN‐93 diet containing 6 mg Cu/kg diet, which is the adequate level of Cu for mice according to the Dietary Reference Intakes (DRI) established by the Food and Nutritional Board of the Institute of Medicine and is equivalent to the current DRI for humans (0.9 mg Cu/day). Four wks after the AAC surgery, some mice were switched to a diet containing 20 mg Cu/kg while others remained on the original 6 mg Cu/kg diet. Then 8 wks after the AAC, all of the mice were harvested for analyses. Heart hypertrophy developed and cardiac contractile dysfunction occurred 4 wks after AAC and further progressed in mice fed 6 mg Cu/kg diet for another 4 wks. But 4 wks after the AAC‐treated mice were switched to 20 mg Cu/kg diet (6 mg × 4wks > 20 mg × 4 wks Cu/kg), the hypertrophic cardiomyopathy was almost completely reversed. Sustained pressure overload leads to decreases in cardiac Cu and suppression of cytochrome c oxidase (CCO) activity along with mitochondropathy. The protein levels of CCO subunit Va and VIb were significantly decreased in sustained pressure overload hearts. Cu supplementation replenishes Cu and recovered CCO activity along with regression of mitochondropathy. The CCO Va and VIb protein levels were also normalized. Therefore, dietary Cu supplementation improves the condition of hypertrophic cardiomyopathy along with recovery of CCO activity and reversal of mitochondropathy in the presence of sustained pressure overload. Supported in part by NIH grants HL59225 and HL63760.