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.