High molecular weight calmodulin-binding protein: 20 years onwards-a potential therapeutic calpain inhibitor.

Apoptosis in cardiovascular diseases is considered to be a major reason for heart failure. Caspase-independent apoptosis due to calpains and other proteases occurs due to increase in intracellular Ca(2+) levels which act on a feed-forward mechanism. Calpains are Ca(2+)-activated cysteine proteases present in the cytosol as inactive proenzymes. Calpastatin is most efficient and specific calpain inhibitor present in vivo. Earlier, we had reported the expression of novel high molecular weight calmodulin-binding protein (HMWCaMBP) in human and animal cardiac tissue and in very minute quantities in brains and lungs. HMWCaMBP showed calpastatin activity and was also found to be highly homologous to calpastatin I and calpastatin II. Decreased expression of HMWCaMBP was observed during ischemia as it is susceptible to proteolysis by calpains during ischemia-reperfusion. In normal myocardium, HMWCaMBP may protect its substrate from calpains. However, during an early stage of ischemia/reperfusion due to increased Ca(2+) influx, calpain activity often exceeds HMWCaMBP activity. This leads to proteolysis of HMWCaMBP and other protein substrates, resulting in cellular damage. The role of HMWCaMBP in ischemia/reperfusion is yet to be elucidated. The present review summarizes the developments in area of HMWCaMBP from the authors' laboratory and its potential for therapy.