Copyright © 2007, European Society of Cardiology
Protecting ischemic hearts by modulation of SR calcium handling
Sapporo Medical University, Departments of Pharmacology and Internal Medicine, S1 W16, Chuo-ku Sapporo, 060-8556, Japan
* Corresponding author. Tel.: +81 11 611 2111 ex2721; fax: +81 11 644 7958. tannom{at}sapmed.ac.jp
Received 27 May 2007; accepted 14 June 2007
See article by Zhou et al. [4] (pages 487–497) in this issue.
The sarcoplasmic reticulum (SR) plays a crucial role in excitation-contraction coupling by regulating the concentration and distribution of intracellular Ca2+. The functions of the SR are known to be compromised by ischemia/reperfusion, but whether SR dysfunction contributes to Ca2+ overload and injury in cardiomyocytes during ischemia/reperfusion has been controversial for a decade. Studies using isolated cardiomyocytes subjected to simulated ischemia/reperfusion generally support the role of the SR in Ca2+ overload at the time of "reperfusion" [1]. However, findings in earlier studies, which examined the effects of ischemia on the SR Ca2+ uptake and Ca2+ release using isolated SR preparations from whole hearts, are contradictory. A study by Chen et al. [2] assessed the Ca2+ concentration in the SR by 19F-NMR in isolated beating hearts and showed that it was well maintained during a 25-min period of ischemia, while the cytosolic Ca2+ level was significantly increased after the onset of ischemia. Furthermore, calculation of the free energy for Ca2+-ATPase and for ATP hydrolysis suggests that the 
GATP is adequate to prevent a net release of SR Ca2+ during a 30-min period of ischemia [2]. However, two inhibitors of Ca2+-ATPase, cyclopiazonic acid and thapsigargin, administered before ischemia or at the time of reperfusion improved recovery of mechanical function in isolated rat hearts [3], suggesting that inhibition of intracellular Ca2+ oscillations and/or depletion of Ca2+ in the SR afford the cardioprotection. These apparent inconsistencies in earlier findings in vitro and in vivo have not been explained and clearly indicate the need for better models to explore the roles of the SR in Ca2+ overload and ischemia/reperfusion injury.
In this issue of the Journal, Zhou et al. [4] report a study using a novel mouse model for exploring the role of SR Ca2+ handling in myocardial ischemia/reperfusion injury. They developed mice overexpressing histidine-rich Ca2+-binding protein (HRC), which is, like calsequestrin, localizes in the SR lumen and binds Ca2+ with high capacity and low affinity [5]. It also binds to triadin, a regulator of SR Ca2+ release [6]. Although HRC only accounts for approximately 1% of junctional SR proteins, while calsequestrin is far more abundant [7], overexpression of HRC by about threefold substantially reduced Ca2+ uptake rate in the SR [8]. Interestingly, Ca2+ influx through the sarcolemma via the Na+-Ca2+ exchanger (NCX) is also suppressed in HRC-overexpressing hearts, which would counteract the reduced SR Ca2+ uptake rate and result in a normal SR Ca2+ store [8]. In this model, myocardial necrosis and apoptosis during ischemia/reperfusion were significantly attenuated compared with those in wild-type mice [4]. These results are consistent with earlier findings in phospholamban (PLN)-knockout mice [9,10]. In the basal, dephosphorylated state, PLN inhibits Ca2+ uptake by the SR, and ablation of this SR protein increased SR Ca2+ uptake and release [9], leading to significantly augmented myocardial injury during ischemia/reperfusion [10]. The findings from these two models of SR protein modulation strongly support the notion that alterations in SR Ca2+ handling by ischemia/reperfusion contributes to myocardial injury in vivo.
Mechanisms by which tolerance against ischemia/reperfusion injury is increased by HRC overexpression and decreased by PLN ablation remain unclear. It is possible that the rate of SR Ca2+ uptake and level of SR Ca2+ stores are determinants of the extent of Ca2+ oscillation and thus cell injury during ischemia/reperfusion. However, their relationships under the conditions of ischemia/reperfusion have not been investigated in HRC-overexpressed and PLN-ablated mice. It is also possible that anti-infarct tolerance in HRC-overexpressed mice is induced, at least in part, by changes secondary to HRC overexpression such as suppressed Ca2+ flux through NCX and upregulation of triadin protein. Although NCX is a major route for Ca2+ efflux under physiological conditions, its reverse-mode operation accelerated by intracellular Na+ accumulation plays a major role in Ca2+ overload during ischemia/reperfusion [11]. Suppression of Na+ overload by inhibiting the Na+–H+ exchanger (NHE) or the Na+ channel has been shown to attenuate Ca2+ overload and myocardial injury after ischemia/reperfusion [12,13]. Inhibition of NCX at the time of reperfusion [14] and cardiac-specific ablation of NCX [15] also attenuate ischemia/reperfusion injury. Thus, reduced NCX activity may be responsible for myocardial resistance to ischemia/reperfusion injury in HRC-overexpressed mice, though alteration in reverse-mode function of NCX in this mouse model has not been characterized.
The main hurdle for the clinical application of HRC up-regulation for management of coronary artery disease is the increased susceptibility of HRC-overexpressing hearts to hypertrophy and heart failure [8]. Indeed, overexpression of HRC compromised the heart's responses to both hemodynamic overload and aging, resulting in congestive heart failure by 18 months of age. However, in contrast to 3-fold overexpression, 2-fold overexpression of HRC in hearts did not induce a cardiomyopathic phenotype during aging [8], indicating that there may be a threshold level of HRC abundance for heart failure development. On the other hand, the threshold of HRC protein level for augmentation of anti-infarct tolerance also remains unclear. Even if a lower level of HRC overexpression protects cardiomyocytes without exposing the heart to the risk of heart failure, the development of a clinical method for controlling up-regulation of HRC is a great challenge. Nevertheless, the study by Zhou et al. [4] has shed light on an interesting target in the SR for myocardial protection against ischemia/reperfusion.
 |
References |
|---|
 Top References |
|---|
- Piper H.M., Kasseckert S., Abdallah Y. The sarcoplasmic reticulum as the primary target of reperfusion protection. Cardiovasc Res (2006) 70:170–173.
[Free Full Text] - Chen W., Steenbergen C., Levy L.A., Vance J., London R.E., Murphy E. Measurement of free Ca2+ in sarcoplasmic reticulum in perfused rabbit heart loaded with 1,2-bis(2-amino-5,6-difluorophenoxy)ethane-N,N,N',N'-tetraacetic acid by 19F NMR. J Biol Chem (1996) 271:7398–7403.
[Abstract/Free Full Text] - du Toit E.F., Opie L.H. Inhibitors of Ca2+ ATPase pump of sarcoplasmic reticulum attenuate reperfusion stunning in isolated rat heart. J Cardiovasc Pharmacol (1994) 24:678–684.[CrossRef][Web of Science][Medline]
- Zhou X., Fan G.C., Ren X., Waggoner J.R., Gregory K.N., Chen G., et al. Overexpression of histidine-rich Ca-binding protein protects against ischemia/reperfusion-induced cardiac injury. Cardiovasc Res (2007) 75:487–497.
[Abstract/Free Full Text] - Lee H.G., Kang H., Kim D.H., Park W.J. Interaction of HRC (histidine-rich Ca2+-binding protein) and triadin in the lumen of sarcoplasmic reticulum. J Biol Chem (2001) 276:39533–39538.
[Abstract/Free Full Text] - Bers D.M. Macromolecular complexes regulating cardiac ryanodine receptor function. J Mol Cell Cardiol (2004) 37:417–429.
- Beard N.A., Laver D.R., Dulhunty A.F. Calsequestrin and the calcium release channel of skeletal and cardiac muscle. Prog Biophys Mol Biol (2004) 85:33–69.[CrossRef][Web of Science][Medline]
- Gregory K.N., Ginsburg K.S., Bodi I., Hahn H., Marreez Y.M., Song Q., et al. Histidine-rich Ca binding protein: a regulator of sarcoplasmic reticulum calcium sequestration and cardiac function. J Mol Cell Cardiol (2006) 40:653–665.[CrossRef][Web of Science][Medline]
- Wolska B.M., Stojanovic M.O., Luo W., Kranias E.G., Solaro R.J. Effect of ablation of phospholamban on dynamics of cardiac myocyte contraction and intracellular Ca2+. Am J Physiol (1996) 271:C391–C397.[Web of Science][Medline]
- Cross H.R., Kranias E.G., Murphy E., Steenbergen C. Ablation of PLB exacerbates ischemic injury to a lesser extent in female than male mice: protective role of NO. Am J Physiol Heart Circ Physiol (2003) 284:H683–H690.
[Abstract/Free Full Text] - Piper H.M., Abdallah Y., Schafer C. The first minutes of reperfusion: a window of opportunity for cardioprotection. Cardiovasc Res (2004) 61:365–371.
[Abstract/Free Full Text] - Miura T., Ogawa T., Suzuki K., Goto M., Shimamoto K. Infarct size limitation by a new Na+–H+ exchange inhibitor, Hoe 642: difference from preconditioning in the role of protein kinase C. J Am Coll Cardiol (1997) 29:693–701.[Abstract]
- Eng S., Maddaford T.G., Kardami E., Pierce G.N. Protection against myocardial ischemic/reperfusion injury by inhibitors of two separate pathways of Na+ entry. J Mol Cell Cardiol (1998) 30:829–835.[CrossRef][Web of Science][Medline]
- Inserte J., Garcia-Dorado D., Ruiz-Meana M., Padilla F., Barrabes J.A., Pina P., et al. Effect of inhibition of Na+/Ca2+ exchanger at the time of myocardial reperfusion on hypercontracture and cell death. Cardiovasc Res (2002) 55:739–748.
[Abstract/Free Full Text] - Imahashi K., Pott C., Goldhaber J.I., Steenbergen C., Philipson K.D., Murphy E. Cardiac-specific ablation of the Na+–Ca2+ exchanger confers protection against ischemia/reperfusion injury. Circ Res (2005) 97:916–921.
[Abstract/Free Full Text]
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||