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

Authors

  • Chang Sik Park
    • School of Life Sciences and Systems Biology Research CenterGwangju Institute of Science and Technology (GIST)
  • Shan Chen
    • Department of Pharmacology and Cell BiophysicsUniversity of Cincinnati College of Medicine
  • Hoyong Lee
    • School of Life Sciences and Systems Biology Research CenterGwangju Institute of Science and Technology (GIST)
  • Hyeseon Cha
    • School of Life Sciences and Systems Biology Research CenterGwangju Institute of Science and Technology (GIST)
  • Jae Gyun Oh
    • School of Life Sciences and Systems Biology Research CenterGwangju Institute of Science and Technology (GIST)
  • Sunghee Hong
    • School of Life Sciences and Systems Biology Research CenterGwangju Institute of Science and Technology (GIST)
  • Peidong Han
    • Department of Pharmacology and Cell BiophysicsUniversity of Cincinnati College of Medicine
  • Kenneth S. Ginsburg
    • Department of PharmacologyUniversity of California Davis
  • Sora Jin
    • School of Life Sciences and Systems Biology Research CenterGwangju Institute of Science and Technology (GIST)
  • Inju Park
    • School of Life Sciences and Systems Biology Research CenterGwangju Institute of Science and Technology (GIST)
  • Vivek P. Singh
    • Department of Pharmacology and Cell BiophysicsUniversity of Cincinnati College of Medicine
  • Hong-Sheng Wang
    • Department of Pharmacology and Cell BiophysicsUniversity of Cincinnati College of Medicine
  • Clara Franzini-Armstrong
    • Department of Cell and Developmental BiologyUniversity of Pennsylvania
  • Woo Jin Park
    • School of Life Sciences and Systems Biology Research CenterGwangju Institute of Science and Technology (GIST)
  • Donald M. Bers
    • Department of PharmacologyUniversity of California Davis
    • Department of Pharmacology and Cell BiophysicsUniversity of Cincinnati College of Medicine
    • Molecular Biology Division, Center for Basic ResearchFoundation for Biomedical Research of the Academy of Athens
    • School of Life Sciences and Systems Biology Research CenterGwangju Institute of Science and Technology (GIST)
    • School of Life Sciences and Systems Biology Research CenterGwangju Institute of Science and Technology (GIST)
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)
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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)
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Supplementary material 5 (TIFF 140 kb)

Copyright information

© Springer-Verlag Berlin Heidelberg 2013