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01-05-2013 | Original Contribution

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, 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

Published in: Basic Research in Cardiology | Issue 3/2013

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.

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Title: 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
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
Publication date: 01-05-2013
Publisher: Springer-Verlag
Published in: Basic Research in Cardiology / Issue 3/2013
Print ISSN: 0300-8428
Electronic ISSN: 1435-1803
DOI: https://doi.org/10.1007/s00395-013-0344-2

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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

Abstract

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