Overexpression of histidine-rich Ca-binding protein protects against ischemia/reperfusion-induced cardiac injury

Zhou, Xiaoyang; Fan, Guo-Chang; Ren, Xiaoping; Waggoner, Jeanne G.; Gregory, Kimberly N.; Chen, Guoli; Jones, W. Keith; Kranias, Evangelia G.

doi:10.1016/j.cardiores.2007.04.005

Cited by 25 publications

(21 citation statements)

References 40 publications

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“…According to previous reports, the expression levels of HRC are significantly decreased in human and mouse models of heart failure [12] and overexpression of HRC protects against ischemia/reperfusion-induced cardiac injury [50]. Thus, it is likely that the expression level of HRC is closely associated with the pathological state of the heart.…”

Section: Discussionmentioning

confidence: 95%

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

et al. 2013

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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 after depolarizations (DADs) 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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Section: Discussionmentioning

confidence: 95%

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

et al. 2013

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“…Interestingly, HRC overexpression was associated with significantly improved recovery of post-ischemic contractile function compared to wild type mouse hearts, while the myocardial infract size was smaller, both ex vivo and in vivo [19]. In addition, the HRC transgenic animals exhibited attenuated ischemia/reperfusion-induced apoptosis, compared to wild types.…”

Section: Histidine-rich Calcium-binding Protein (Hrc)mentioning

confidence: 99%

“…This increase of the Bcl-2/Bax ratio may be the result of the decreased free [Ca 2+ ] SR due to HRC overexpression, which leads to reduced intramitochondrial Ca 2+ -accumulation. Furthermore, the active caspase-3, caspase-9 and caspase-12 were markedly decreased in transgenic hearts after ischemia/reperfusion, possibly due to increased cytosolic Ca 2+ -levels [19]. These data suggest that inhibition of apoptotic cell death is the mechanism of protection against cardiac ischemia/reperfusion injury in HRC overexpressing animals.…”

Section: Histidine-rich Calcium-binding Protein (Hrc)mentioning

confidence: 99%

“…Functionally, HRC has an important role in SR Ca 2+ -handling and in the overall cardiac physiology as it has been shown to improve the SR Ca 2+ -storage capacity and enhance cardiomyocyte survival after ischemia [19], to alter Ca 2+ -cycling after acute [20] and chronic overexpression [6], and to be implicated in human arrhythmia as a modifying factor [21,22]. …”

Section: Introductionmentioning

confidence: 99%

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Histidine-rich calcium binding protein: The new regulator of sarcoplasmic reticulum calcium cycling

Arvanitis

Vafiadaki

Sanoudou

et al. 2011

Journal of Molecular and Cellular Cardiology

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The histidine-rich calcium binding protein (HRC) is a novel regulator of sarcoplasmic reticulum (SR) Ca 2+ -uptake, storage and release. Residing in the SR lumen, HRC binds Ca 2+ with high capacity but low affinity. In vitro phosphorylation of HRC affects ryanodine affinity of the ryanodine receptor (RyR), suggesting a functional role of HRC on SR Ca 2+ -release. Indeed, acute HRC overexpression in isolated rodent cardiomyocytes decreases Ca 2+ -induced Ca 2+ -release, increases SR Ca 2+ -load, and impairs contractility. The HRC effects on RyR may be regulated by the Ca 2+ -sensitivity of its interaction with triadin. However, HRC also affects the SR Ca 2+ -ATPase, as shown by HRC overexpression in transgenic mouse hearts, which resulted in reduced SR Ca 2+ -uptake rates, cardiac remodeling and hypertrophy. In fact, in vitro generated evidence suggests that HRC directly interacts with SR Ca 2+ -ATPase2, supporting a dual role of HRC in Ca 2+ -homeostasis: regulation of both SR Ca 2+ -uptake and Ca 2+ -release. Furthermore, HRC plays an important role in myocyte differentiation and in antiapoptotic cardioprotection against ischemia/reperfusion induced cardiac injury. Interestingly, HRC has been linked with familiar cardiac conduction disease and an HRC polymorphism was shown to associate with malignant ventricular arrhythmias in the background of idiopathic dilated cardiomyopathy. This review summarizes studies, which have established the critical role of HRC in Ca 2+ -homeostasis, suggesting its importance in cardiac physiology and pathophysiology.

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“…HRC also interacts with SERCA in cardiac muscle (Arvanitis et al 2007), leading to the intriguing hypothesis that HRC may link Ca 2þ release (via triadin) and Ca 2þ uptake (via SERCA) in the SR lumen (Pritchard and Kranias 2009). HRC is implicated in cardiovascular disease: overexpression (gain-of-function) of HRC provides protection against heart damage induced by ischemia/reperfusion (Zhou et al 2007) whereas a S 96 A mutation in HRC has been identified in human patients to correlate with decreased survival in idiopathic dilated cardiomyopathy (Arvanitis et al 2008). Mice deficient (loss-of-function) in HRC are more liable to develop cardiac hypertrophy when treated with isoproterenol (Jaehnig et al 2006).…”

Section: Minor Sr Ca 2þ Buffering Proteinsmentioning

confidence: 99%

Organellar Calcium Buffers

Prins¹,

Michalak²

2011

Cold Spring Harbor Perspectives in Biology

119

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Overexpression of histidine-rich Ca-binding protein protects against ischemia/reperfusion-induced cardiac injury

Abstract: Our findings suggest that increased cardiac HRC expression protects against ischemia/reperfusion injury in the heart, resulting in improved recovery of function and reduced infarction.

Cited by 25 publications

References 40 publications

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

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

Histidine-rich calcium binding protein: The new regulator of sarcoplasmic reticulum calcium cycling

Organellar Calcium Buffers

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