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

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

The histidine-rich Ca2+-binding protein (HRC) is located in the lumen of the sarcoplasmic reticulum (SR) and exhibits high-capacity Ca 2+-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.

Original languageEnglish (US)
Article number346
JournalBasic Research in Cardiology
Volume108
Issue number3
DOIs
StatePublished - 2013

Keywords

  • Calcium cycling
  • Fibrosis
  • Heart failure
  • Hypertrophy
  • Pulmonary edema
  • Sarcoplasmic reticulum

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)
  • Physiology

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    Park, C. S., Chen, S., Lee, H., Cha, H., Oh, J. G., Hong, S., Han, P., Ginsburg, K. S., Jin, S., Park, I., Singh, V. P., Wang, H. S., Franzini-Armstrong, C., Park, W. J., Bers, D. M., Kranias, E. G., Cho, C., & Kim, D. H. (2013). 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. Basic Research in Cardiology, 108(3), [346]. https://doi.org/10.1007/s00395-013-0344-2