HRC is a high capacity Ca2+ binding protein located in the lumen of sarcoplasmic reticulum (SR). Previously, we had shown that HRC knock-down not only led to enhanced Ca2+ release and Ca2+ uptake in SR, but exacerbated cardiac function after transverse aortic constriction (TAC), suggesting its important role in Ca2+ cycling and cardiac function. HRC-KO mice were generated and used for the present study. Pressure overload induced by TAC in the KO mice heart resulted in severe cardiac hypertrophy with 27% increase of heart weight (HW) per body weight (BW) ratio and 25% increase of tibia length per BW ratio as compared to WT TAC mice. HRC KO mice also showed decreased fractional shortening (FS) by 37%, increased TGF-β expression by 2 folds, severe cardiac fibrosis and highly increased number of TUNEL positive signals in heart tissue compared to WT TAC mice. The electrocardiogram (ECG) study showed shorter RR interval, faster heart rate and decreased R amplitude in HRC KO TAC mice. The incidence of arrhythmia was significantly increased in HRC KO mice after intraperitoneal injection of caffeine (120 mg/kg BW) and epinephrine (2 mg/kg BW),indicating that HRC KO mice are more susceptible to epinephrine and caffeine injection, consistent with the previous report (Jaehnig et al. Mol. Cell. Biol., 2006). The survival rate of HRC KO mice was significantly decreased after TAC. Taken together, our results suggest that ablation of HRC could lead to altered SR Ca2+ cycling and deterioration of cardiac function under pathological condition. (Supported by Korea MEST NRF Grant (20110002144), the 2011 GIST System Biology Infrastructure Establishment Grant and KISTI-KREONET).