High molecular weight calmodulin-binding protein: 20 years onwards-a potential therapeutic calpain inhibitor
Cardiovascular Drugs and Therapy, 06/01/2012
Parameswaran S et al. – The present review summarizes the developments in area of HMWCaMBP from the authors' laboratory and its potential for therapy.
- 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 Ca2+ levels which act on a feed–forward mechanism.
- Calpains are Ca2+–activated cysteine proteases present in the cytosol as inactive proenzymes.
- Calpastatin is most efficient and specific calpain inhibitor present in vivo.
- Earlier, authors 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 Ca2+ 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.