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http://purl.uniprot.org/citations/22952658http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/22952658http://www.w3.org/2000/01/rdf-schema#comment"

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."xsd:string
http://purl.uniprot.org/citations/22952658http://purl.org/dc/terms/identifier"doi:10.1371/journal.pone.0043282"xsd:string
http://purl.uniprot.org/citations/22952658http://purl.uniprot.org/core/author"Kim D.H."xsd:string
http://purl.uniprot.org/citations/22952658http://purl.uniprot.org/core/author"Park C.S."xsd:string
http://purl.uniprot.org/citations/22952658http://purl.uniprot.org/core/author"Cho C."xsd:string
http://purl.uniprot.org/citations/22952658http://purl.uniprot.org/core/author"Jeong D."xsd:string
http://purl.uniprot.org/citations/22952658http://purl.uniprot.org/core/author"Kwon E.J."xsd:string
http://purl.uniprot.org/citations/22952658http://purl.uniprot.org/core/author"Park W.J."xsd:string
http://purl.uniprot.org/citations/22952658http://purl.uniprot.org/core/author"Kranias E.G."xsd:string
http://purl.uniprot.org/citations/22952658http://purl.uniprot.org/core/author"Cha H."xsd:string
http://purl.uniprot.org/citations/22952658http://purl.uniprot.org/core/author"Hajjar R.J."xsd:string
http://purl.uniprot.org/citations/22952658http://purl.uniprot.org/core/date"2012"xsd:gYear
http://purl.uniprot.org/citations/22952658http://purl.uniprot.org/core/name"PLoS One"xsd:string
http://purl.uniprot.org/citations/22952658http://purl.uniprot.org/core/pages"e43282"xsd:string
http://purl.uniprot.org/citations/22952658http://purl.uniprot.org/core/title"AAV-mediated knock-down of HRC exacerbates transverse aorta constriction-induced heart failure."xsd:string
http://purl.uniprot.org/citations/22952658http://purl.uniprot.org/core/volume"7"xsd:string
http://purl.uniprot.org/citations/22952658http://www.w3.org/2004/02/skos/core#exactMatchhttp://purl.uniprot.org/pubmed/22952658
http://purl.uniprot.org/citations/22952658http://xmlns.com/foaf/0.1/primaryTopicOfhttps://pubmed.ncbi.nlm.nih.gov/22952658
http://purl.uniprot.org/uniprot/A6JB07#attribution-AC7A60647EFADD0E818829EA498301F7http://purl.uniprot.org/core/sourcehttp://purl.uniprot.org/citations/22952658
http://purl.uniprot.org/uniprot/A0A8I5ZZ96#attribution-AC7A60647EFADD0E818829EA498301F7http://purl.uniprot.org/core/sourcehttp://purl.uniprot.org/citations/22952658
http://purl.uniprot.org/uniprot/A6JB08#attribution-AC7A60647EFADD0E818829EA498301F7http://purl.uniprot.org/core/sourcehttp://purl.uniprot.org/citations/22952658
http://purl.uniprot.org/uniprot/A6JB09#attribution-AC7A60647EFADD0E818829EA498301F7http://purl.uniprot.org/core/sourcehttp://purl.uniprot.org/citations/22952658
http://purl.uniprot.org/uniprot/G3V8S6#attribution-AC7A60647EFADD0E818829EA498301F7http://purl.uniprot.org/core/sourcehttp://purl.uniprot.org/citations/22952658
http://purl.uniprot.org/uniprot/A0A8I6AUL9#attribution-AC7A60647EFADD0E818829EA498301F7http://purl.uniprot.org/core/sourcehttp://purl.uniprot.org/citations/22952658
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