Calcium (Ca(2+)) recycling is key for effective relaxation of the cardiac muscle. Failure to properly recycle calcium through the sarcoplasmic reticulum (SR) results in severe impairment of myocardial relaxation and consequently alteration of the "beat-to-beat" heart rhythm and contractile function. The Sarco(Endo)plasmic reticulum Ca(2+) ATPase (SERCA) is instrumental for recycling cytosolic Ca(2+) into the lumen of the SR. Among the many SERCA isoforms identified so far, SERCA2a is restricted to slow-twitch skeletal and cardiac muscle, while SERCA2b is ubiquitously expressed. SERCA2a/b expression and activity are altered in major heart diseases such as ischemic heart disease, cardiomyopathies and congestive heart failure. Restoring adequate SERCA2a/b expression by pharmacological action or gene delivery has emerged as a new approach for the treatment of heart failure. In this review we describe the drugs adopted in clinical practice that activate SERCA2a/b function as well as new promising therapeutic tools using SERCA2 viral gene delivery to improve cardiac function and treat heart failure.
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