Ageing, gender and cardiac sarcolemmal KATP channels

Sarcolemmal ATP-sensitive K(+) (K(ATP)) channels are abundant in cardiac myocytes where they couple the cellular metabolic state with membrane excitability. Structurally, these channels are composed of Kir6.2, a pore-forming subunit, SUR2A, a regulatory subunit, and at least four accessory proteins. The activation of K(ATP) channels occurs during ischaemia to promote cardiac viability under this adverse condition. Age-dependent changes in the myocardial susceptibility to ischaemia have been reported in experimental animals as well as in humans. Recent research has demonstrated that ageing is associated with a decrease in the number of cardiac sarcolemmal K(ATP) channels in hearts from females, but not males. This alteration is likely to be due to an age-dependent decrease in the concentration of circulating estrogens. In the heart, SUR2A is the least expressed protein of all K(ATP) channel-forming proteins. The consequence of this phenomenon is that the level of SUR2A is the main factor controlling the number of sarcolemmal K(ATP) channels. Estrogens specifically up-regulate SUR2A and govern the number of sarcolemmal K(ATP) channels, and this may explain the effect of decreasing estrogen levels on the heart. An age-dependent decrease in the number of sarcolemmal K(ATP) channels generates a cardiac phenotype more sensitive to ischaemia, which seems to be responsible for the ageing-associated decrease in myocardial tolerance to stress that occurs in elderly women.