Calpain plays an important role in
myocardial ischemia/reperfusion (I/R) injury.
PD150606, a nonpeptide, cell-permeable and noncompetitive
calpain inhibitor, has been shown to have protective properties in ischemic disease. The aims of the present study were to investigate whether
PD150606 could alleviate myocardial I/R injury and to examine the possible mechanisms involved. The I/R model was established in vivo in C57BL/6 mice and in vitro using neonatal mouse cardiomyocytes, respectively. To evaluate the protective effects of
PD150606 on I/R injury, we measured the
myocardial infarct area, apoptosis, and expression of cleaved
caspase-3. We also investigated the underlying mechanisms by examining mitochondrial function as reflected by the
ATP concentration, translocation of
cytochrome c, dynamics of
mPTP opening, and membrane potential (ΔΨm), coupled with
calpain activity. Pretreatment with
PD150606 significantly reduced the
infarct area and apoptosis caused by I/R.
PD150606 pretreatment also reduced
mitochondrial dysfunction by inhibiting
calpain activation. Moreover, we found that μ-
calpain is the main contributor to I/R-induced
calpain activation. Knockdown of μ-
calpain with
siRNA significantly reversed
calpain activation,
mitochondrial dysfunction, and cardiomyocyte apoptosis caused by I/R in vitro. Our results suggest that
PD150606 may protect against I/R injury via preventing μ-
calpain-induced mitochondrial apoptosis.