Enhanced gene expression of Na+/Ca2+ exchanger attenuates ischemic and hypoxic contractile dysfunction

Enhanced gene expression of the Na+/Ca2+ exchanger in failing hearts may be a compensatory mechanism to promote influx and efflux of Ca2+, despite imp airment of the sarcoplasmic reticulum (SR). To explore this, we monitored i ntracellular calcium (Ca-i(2+)) and cardiac function in mouse hearts engine ered to overexpress the Na+/Ca2+ exchanger and subjected to ischemia and hy poxia, conditions known to impair SR Ca-i(2+) transport and contractility. Although baseline Ca-i(2+) and function were similar between transgenic and wild-type hearts, significant differences were observed during ischemia an d hypoxia. During early ischemia, Ca-i(2+) was preserved in transgenic hear ts but significantly altered in wild-type hearts. Transgenic hearts maintai ned 40% of pressure-generating capacity during early ischemia, whereas wild -type hearts maintained only 25% (P < 0.01). During hypoxia, neither peak n or diastolic Ca-i(2+) decreased in transgenic hearts. In contrast, both pea k and diastolic Ca-i(2+) decreased significantly in wild-type hearts. The d ecline of Ca-i(2+) was abbreviated in hypoxic transgenic hearts but prolong ed in wild-type hearts. Peak systolic pressure decreased by nearly 10% in h ypoxic transgenic hearts and >25% in wild-type hearts (P < 0.001). These da ta demonstrate that enhanced gene expression of the Na+/Ca2+ exchanger pres erves Ca-i(2+) homeostasis during ischemia and hypoxia, thereby preserving cardiac function in the acutely failing heart.