AAV-Mediated Knock-Down of HRC Exacerbates Transverse Aorta Constriction-Induced Heart Failureopen access
- Authors
- Park, Chang Sik; Cha, Hyeseon; Kwon, Eun Jeong; Jeong, Dongtak; Hajjar, Roger J.; Kranias, Evangelia G.; Cho, Chunghee; Park, Woo Jin; Kim, Do Han
- Issue Date
- Aug-2012
- Publisher
- PUBLIC LIBRARY SCIENCE
- Citation
- PLOS ONE, v.7, no.8, pp.1 - 17
- Indexed
- SCIE
SCOPUS
- Journal Title
- PLOS ONE
- Volume
- 7
- Number
- 8
- Start Page
- 1
- End Page
- 17
- URI
- https://scholarworks.bwise.kr/erica/handle/2021.sw.erica/32186
- DOI
- 10.1371/journal.pone.0043282
- ISSN
- 1932-6203
- Abstract
- 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 Ca2+ cycling in the SR. Chronic overexpression of HRC that may disrupt intracellular Ca2+ 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 Ca2+ 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 Ca2+ cycling and increased activities of RyR2 and SERCA2 without change in SR Ca2+ 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 Ca2+ leak and cytosolic Ca2+ 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 Ca2+ cycling.
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