PMID- 22952658
OWN - NLM
STAT- MEDLINE
DCOM- 20130219
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 7
IP  - 8
DP  - 2012
TI  - AAV-mediated knock-down of HRC exacerbates transverse aorta constriction-induced 
      heart failure.
PG  - e43282
LID - 10.1371/journal.pone.0043282 [doi]
LID - e43282
AB  - 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.
FAU - Park, Chang Sik
AU  - Park CS
AD  - College of Life Sciences and Systems Biology Research Center, Gwangju Institute 
      of Science and Technology (GIST), Buk-gu, Gwangju, Republic of Korea.
FAU - Cha, Hyeseon
AU  - Cha H
FAU - Kwon, Eun Jeong
AU  - Kwon EJ
FAU - Jeong, Dongtak
AU  - Jeong D
FAU - Hajjar, Roger J
AU  - Hajjar RJ
FAU - Kranias, Evangelia G
AU  - Kranias EG
FAU - Cho, Chunghee
AU  - Cho C
FAU - Park, Woo Jin
AU  - Park WJ
FAU - Kim, Do Han
AU  - Kim DH
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120828
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Calcium-Binding Proteins)
RN  - 0 (Carrier Proteins)
RN  - 0 (Muscle Proteins)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (triadin)
RN  - 4QD397987E (Histidine)
RN  - EC 3.6.3.8 (Sarcoplasmic Reticulum Calcium-Transporting ATPases)
RN  - L628TT009W (Isoproterenol)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Animals
MH  - Aorta/*pathology
MH  - Calcium/*metabolism
MH  - Calcium-Binding Proteins/genetics/*metabolism
MH  - Cardiomegaly/pathology
MH  - Carrier Proteins/*metabolism
MH  - Constriction
MH  - Cytosol/metabolism
MH  - Dependovirus/*metabolism
MH  - Disease Models, Animal
MH  - Echocardiography/methods
MH  - *Gene Expression Regulation
MH  - Heart/physiology
MH  - Heart Failure/*genetics/physiopathology
MH  - Histidine/*chemistry
MH  - Homeostasis
MH  - Isoproterenol/pharmacology
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Muscle Proteins/*metabolism
MH  - Phenotype
MH  - Phosphorylation
MH  - RNA, Small Interfering/metabolism
MH  - Sarcoplasmic Reticulum/*metabolism
MH  - Sarcoplasmic Reticulum Calcium-Transporting ATPases/*metabolism
PMC - PMC3429470
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2012/09/07 06:00
MHDA- 2013/02/21 06:00
PMCR- 2012/08/28
CRDT- 2012/09/07 06:00
PHST- 2012/03/05 00:00 [received]
PHST- 2012/07/23 00:00 [accepted]
PHST- 2012/09/07 06:00 [entrez]
PHST- 2012/09/07 06:00 [pubmed]
PHST- 2013/02/21 06:00 [medline]
PHST- 2012/08/28 00:00 [pmc-release]
AID - PONE-D-12-06556 [pii]
AID - 10.1371/journal.pone.0043282 [doi]
PST - ppublish
SO  - PLoS One. 2012;7(8):e43282. doi: 10.1371/journal.pone.0043282. Epub 2012 Aug 28.