Basic Research in Cardiology

, 108:344

Targeted ablation of the histidine-rich Ca2+-binding protein (HRC) gene is associated with abnormal SR Ca2+-cycling and severe pathology under pressure-overload stress

  • Chang Sik Park
  • Shan Chen
  • Hoyong Lee
  • Hyeseon Cha
  • Jae Gyun Oh
  • Sunghee Hong
  • Peidong Han
  • Kenneth S. Ginsburg
  • Sora Jin
  • Inju Park
  • Vivek P. Singh
  • Hong-Sheng Wang
  • Clara Franzini-Armstrong
  • Woo Jin Park
  • Donald M. Bers
  • Evangelia G. Kranias
  • Chunghee Cho
  • Do Han Kim
Original Contribution

DOI: 10.1007/s00395-013-0344-2

Cite this article as:
Park, C.S., Chen, S., Lee, H. et al. Basic Res Cardiol (2013) 108: 344. doi:10.1007/s00395-013-0344-2

Abstract

The histidine-rich Ca2+-binding protein (HRC) is located in the lumen of the sarcoplasmic reticulum (SR) and exhibits high-capacity Ca2+-binding properties. Overexpression of HRC in the heart resulted in impaired SR Ca2+ uptake and depressed relaxation through its interaction with SERCA2a. However, the functional significance of HRC in overall regulation of calcium cycling and contractility is not currently well defined. To further elucidate the role of HRC in vivo under physiological and pathophysiological conditions, we generated and characterized HRC-knockout (KO) mice. The KO mice were morphologically and histologically normal compared to wild-type (WT) mice. At the cellular level, ablation of HRC resulted in significantly enhanced contractility, Ca2+ transients, and maximal SR Ca2+ uptake rates in the heart. However, after-contractions were developed in 50 % of HRC-KO cardiomyocytes, compared to 11 % in WT mice under stress conditions of high-frequency stimulation (5 Hz) and isoproterenol application. A parallel examination of the electrical activity revealed significant increases in the occurrence of Ca2+ spontaneous SR Ca2+ release and delayed afterdepolarizations with ISO in HRC-KO, compared to WT cells. The frequency of Ca2+ sparks was also significantly higher in HRC-KO cells with ISO, consistent with the elevated SR Ca2+ load in the KO cells. Furthermore, HRC-KO cardiomyocytes showed significantly deteriorated cell contractility and Ca2+-cycling caused possibly by depressed SERCA2a expression after transverse-aortic constriction (TAC). Also HRC-null mice exhibited severe cardiac hypertrophy, fibrosis, pulmonary edema and decreased survival after TAC. Our results indicate that ablation of HRC is associated with poorly regulated SR Ca2+-cycling, and severe pathology under pressure-overload stress, suggesting an essential role of HRC in maintaining the integrity of cardiac function.

Keywords

Calcium cyclingSarcoplasmic reticulumHypertrophyFibrosisHeart failurePulmonary edema

Supplementary material

395_2013_344_MOESM1_ESM.doc (44 kb)
Supplementary material 1 (DOC 43 kb)
395_2013_344_MOESM2_ESM.tif (907 kb)
Supplementary material 2 (TIFF 907 kb)
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Supplementary material 3 (TIFF 765 kb)
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Supplementary material 4 (TIFF 269 kb)
395_2013_344_MOESM5_ESM.tif (141 kb)
Supplementary material 5 (TIFF 140 kb)

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Chang Sik Park
    • 1
  • Shan Chen
    • 2
  • Hoyong Lee
    • 1
  • Hyeseon Cha
    • 1
  • Jae Gyun Oh
    • 1
  • Sunghee Hong
    • 1
  • Peidong Han
    • 2
  • Kenneth S. Ginsburg
    • 3
  • Sora Jin
    • 1
  • Inju Park
    • 1
  • Vivek P. Singh
    • 2
  • Hong-Sheng Wang
    • 2
  • Clara Franzini-Armstrong
    • 4
  • Woo Jin Park
    • 1
  • Donald M. Bers
    • 3
  • Evangelia G. Kranias
    • 2
    • 5
  • Chunghee Cho
    • 1
  • Do Han Kim
    • 1
  1. 1.School of Life Sciences and Systems Biology Research CenterGwangju Institute of Science and Technology (GIST)GwangjuRepublic of Korea
  2. 2.Department of Pharmacology and Cell BiophysicsUniversity of Cincinnati College of MedicineCincinnatiUSA
  3. 3.Department of PharmacologyUniversity of California DavisDavisUSA
  4. 4.Department of Cell and Developmental BiologyUniversity of PennsylvaniaPhiladelphiaUSA
  5. 5.Molecular Biology Division, Center for Basic ResearchFoundation for Biomedical Research of the Academy of AthensAthensGreece