BACKGROUND: Histidine-rich calcium binding protein (HRC) is located in the lumen 
of sarcoplasmic reticulum (SR) that binds to both triadin (TRN) and SERCA 
affecting Ca(2+) cycling in the SR. Chronic overexpression of HRC that may 
disrupt intracellular Ca(2+) homeostasis is implicated in pathogenesis of 
cardiac hypertrophy. Ablation of HRC showed relatively normal phenotypes under 
basal condition, but exhibited a significantly increased susceptibility to 
isoproterenol-induced cardiac hypertrophy. In the present study, we 
characterized the functions of HRC related to Ca(2+) cycling and pathogenesis of 
cardiac hypertrophy using the in vitro siRNA- and the in vivo adeno-associated 
virus (AAV)-mediated HRC knock-down (KD) systems, respectively.
METHODOLOGY/PRINCIPAL FINDINGS: AAV-mediated HRC-KD system was used with or 
without C57BL/6 mouse model of transverse aortic constriction-induced failing 
heart (TAC-FH) to examine whether HRC-KD could enhance cardiac function in 
failing heart (FH). Initially we expected that HRC-KD could elicit cardiac 
functional recovery in failing heart (FH), since predesigned siRNA-mediated 
HRC-KD enhanced Ca(2+) cycling and increased activities of RyR2 and SERCA2 
without change in SR Ca(2+) load in neonatal rat ventricular cells (NRVCs) and 
HL-1 cells. However, AAV9-mediated HRC-KD in TAC-FH was associated with 
decreased fractional shortening and increased cardiac fibrosis compared with 
control. We found that phospho-RyR2, phospho-CaMKII, phospho-p38 MAPK, and 
phospho-PLB were significantly upregulated by HRC-KD in TAC-FH. A significantly 
increased level of cleaved caspase-3, a cardiac cell death marker was also 
found, consistent with the result of TUNEL assay.
CONCLUSIONS/SIGNIFICANCE: Increased Ca(2+) leak and cytosolic Ca(2+) 
concentration due to a partial KD of HRC could enhance activity of CaMKII and 
phosphorylation of p38 MAPK, causing the mitochondrial death pathway observed in 
TAC-FH. Our results present evidence that down-regulation of HRC could 
deteriorate cardiac function in TAC-FH through perturbed SR-mediated Ca(2+) 
cycling.