Sodium-potassium ATPase modulation for aging related disease - James Larrick
An urgent need exists to develop novel therapies for cardiac failure. The Na+/K+ ATPase (NKA) catalyzes active transport of Na+ and K+ ions across the cardiomyocyte plasma membrane. Cardiac glycosides are classically thought to have a positive inotropic effect by inhibiting NKA which increases intracellular Na+ which is exchanged with Ca++ to augment contractility. Although this mechanism is undoubtedly more complicated (Nishio, 2002), recent work identified an activation site on NKA. An affinity purified antiserum specific for this extracellular site markedly augments NKA catalytic activity both in vitro and in vivo in rodents (Zheng, 2011). The augmented NKA activity is correlated with a positive cardiotonic action and perhaps most importantly activation of cardioprotective pathways in vivo. Spontaneously hypertensive heart failure rats (SHHF) develop a severe, lethal hypertensive cardiomyopathy. High titer anti-NKA antibodies elicited in SHHF by active immunization completely prevented the lethal heart failure (HF) of these animals with no noticeable adverse effects over a period of 30 weeks. Based on these initial proof-of principle studies, we utilized our human Fab phagemid library to identify HuNKA, a high affinity anti-NKA human monoclonal antibody. Our preliminary in vitro studies indicate that HuNKA not only exhibits a positive cardiotonic effect but initiates cardioprotection via activation of extracellular signal-regulated kinase 1/2 and phosphoinositide 3-kinase/Akt pathways. Based on these activities we are optimistic that HuNKA will provide a novel immunotherapeutic approach for heart failure.
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