OBJECTIVE: The histidine-rich Ca-binding protein (HRC) is a Ca-storage protein 
in cardiac sarcoplasmic reticulum. Recent transgenic studies revealed that this 
protein inhibits the maximal rates of sarcoplasmic reticulum Ca-transport, 
leading to cardiac dysfunction. In view of the role of sarcoplasmic reticulum 
Ca-cycling in myocardial ischemia/reperfusion injury, we designed this study to 
gain further insight into the role of HRC during ischemia/reperfusion.
METHODS AND RESULTS: The transgenic mouse model with cardiac-specific 
overexpression of HRC was utilized and cardiac contractile parameters were 
assessed before and after ischemia/reperfusion injury by Langendorff perfusion. 
After a 20-min stabilization period, the hearts were subjected to 40 min of 
global ischemia, followed by 60 min of reperfusion. We found that although 
transgenic (TG) hearts showed depressed cardiac function (25%) compared to wild 
types (WTs) at baseline, they exhibited better recovery of left ventricular 
developed pressure (86.6+/-2.6% in TGs vs. 58.3+/-4.0% in WTs of pre-ischemic 
values, P<0.05) and higher rates of contraction and relaxation after 
ischemia/reperfusion than WTs. This improvement was accompanied by smaller 
infarcts (23.1+/-1.7% in TGs vs. 41.1+/-2.5% in WTs of infarct region-to-risk 
region ratio, P<0.05) and lower creatine kinase release. Notably, the extent of 
apoptotic cell death was significantly attenuated, as evidenced by decreased DNA 
fragmentation, upregulation of the antiapoptotic protein Bcl-2, and 
downregulation of the active caspases (3, 9 and 12) following 
ischemia/reperfusion in TG hearts, compared with WTs. Extension of these studies 
to an in vivo model of 30-min myocardial ischemia, via coronary artery 
occlusion, followed by 24-h reperfusion, showed that the infarct region-to-risk 
region ratio was 9+/-0.9% in TGs, compared with 20.4+/-2.9% in WTs (P<0.05).
CONCLUSIONS: Our findings suggest that increased cardiac HRC expression protects 
against ischemia/reperfusion injury in the heart, resulting in improved recovery 
of function and reduced infarction.