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Am J Physiol Heart Circ Physiol 291: H2008-H2012, 2006. First published May 26, 2006; doi:10.1152/ajpheart.00313.2006
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First molecular evidence that inositol trisphosphate signaling contributes to infarct size reduction with preconditioning

Karin Przyklenk,1,2 Michelle Maynard,1 and Peter Whittaker1,2

Departments of 1Emergency Medicine and 2Anesthesiology, University of Massachusetts Medical School, Worcester Massachusetts

Submitted 27 March 2006 ; accepted in final form 22 May 2006


   ABSTRACT
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 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
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Considerable attention has focused on the role of protein kinase C (PKC) in triggering the profound infarct-sparing effect of ischemic preconditioning (PC). In contrast, the involvement of inositol 1,4,5-trisphosphate [Ins(1,4,5)P3], the second messenger generated in parallel with the diacylglycerol-PKC pathway, remains poorly understood. We hypothesized that, if Ins(1,4,5)P3 signaling [i.e., release of Ins(1,4,5)P3 and subsequent binding to Ins(1,4,5)P3 receptors] contributes to PC-induced cardioprotection, then the reduction of infarct size achieved with PC would be attenuated in mice that are deficient in Ins(1,4,5)P3 receptor protein. To test this concept, hearts were harvested from 1) B6C3Fe-a/a-Itpr-1opt+/–/J mutants displaying reduced expression of Ins(1,4,5)P3 receptor-1 protein, 2) Itpr-1opt+/+ wild types from the colony, and 3) C57BL/6J mice. All hearts were buffer-perfused and randomized to receive two 5-min episodes of PC ischemia, pretreatment with D-myo-Ins(1,4,5)P3 [sodium salt of native Ins(1,4,5)P3], the mitochondrial ATP-sensitive K+ channel opener diazoxide, or no intervention (controls). After the treatment phase, all hearts underwent 30-min global ischemia followed by 2 h of reperfusion, and infarct size was delineated by tetrazolium staining. In both wild-type and C57BL/6J cohorts, area of necrosis in hearts that received PC, D-myo-Ins(1,4,5)P3, and diazoxide averaged 28–35% of the total left ventricle (LV), significantly smaller than the values of 52–53% seen in controls (P < 0.05). In contrast, in Itpr-1opt+/– mutants, protection was only seen with diazoxide: neither PC nor D-myo-Ins(1,4,5)P3 limited infarct size (52–58% vs. 56% of the LV in mutant controls). These data provide novel evidence that Ins(1,4,5)P3 signaling contributes to infarct size reduction with PC.

myocardial ischemia; myocardial infarction; signal transduction; inositol 1,4,5-trisphosphate

PRECONDITIONING (PC) is the well-described phenomenon whereby brief episodes of myocardial ischemia render the heart resistant to a subsequent, sustained ischemic insult (21, 29). Among the multiple, complex mechanisms that purportedly contribute to the profound infarct-sparing effect of PC, considerable attention has focused on the pivotal role of protein kinase C (PKC) in triggering the preconditioned state (6, 29). In contrast, the involvement of inositol 1,4,5-trisphosphate [Ins(1,4,5)P3], the second messenger generated in parallel with the diacylglycerol-PKC pathway, remains poorly understood. Specifically, while preischemic administration of exogenous Ins(1,4,5)P3 [i.e., D-myo-Ins(1,4,5)P3 hexasodium] has been shown to evoke a reduction of infarct size comparable in magnitude to that achieved with PC (9, 22, 23), and indirect evidence has implicated the possible involvement of native Ins(1,4,5)P3 in PC- and opioid-induced cardioprotection (1, 2), efforts to gain definitive insight into this issue have been confounded by the lack of selective and short-acting Ins(1,4,5)P3 antagonists (4). We hypothesized that, if Ins(1,4,5)P3 signaling [that is, release of Ins(1,4,5)P3 and subsequent binding to Ins(1,4,5)P3 receptors] contributes to infarct size reduction with PC, then the infarct-sparing effect of PC would be attenuated in mice that are deficient in Ins(1,4,5)P3 receptor protein. Accordingly, our goal was to test this concept in mice displaying a defect in the Ins(1,4,5)P3 receptor-1 gene (Itpr-1opt).


   MATERIALS AND METHODS
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This study was approved by the Institutional Animal Care and Use Committee of the University of Massachusetts Medical School and was performed in accordance with the Guide for the Care and Use of Laboratory Animals from the Institute of Laboratory Animals Resources (NIH Publication Vol. 25, No. 28, Revised 1996).

Experiments were conducted using adult (3–4 mo old) B6C3Fe-a/a-Itpr-1opt+/–/J mice heterozygous for the opisthotonus spontaneous mutation (purchased from The Jackson Laboratory, Bar Harbor, ME). Mutant Itpr-1opt+/– mice are reportedly characterized by a reduced expression of Ins(1,4,5)P3 receptor-1 protein and loss of modulatory sites (26). Of note, heterozygous Itpr-1opt+/– mice were utilized, as animals homozygous for the spontaneous mutation die soon after birth (16). Concurrent experiments were performed in two age-matched control cohorts: wild-type Itpr-1opt+/+ mice from the colony (The Jackson Laboratory) and a standard population of C57BL/6J mice.

Characterization of Itpr-1opt+/– mice. To gain initial insight into the phenotype of the Itpr-1opt+/– mutants, mice from each of the three cohorts were anesthetized with pentobarbital sodium (60 mg/kg ip) and 1) the hearts and brains were rapidly excised, snap-frozen in liquid nitrogen, and used for detection (by standard immunoblotting) of Ins(1,4,5)P3 receptor-1 protein (n = 3 per cohort); or 2) the hearts were harvested for histological assessment of myocyte size and myocardial fibrosis (n = 4).

Infarct size protocol. Myocardial infarct size, our primary study endpoint, was assessed using the isolated buffer-perfused heart model. In brief, Itpr-1opt+/– mutants (n = 24), Itpr-1opt+/+ wild types (n = 24), and C57BL/6J mice (n = 32) were anesthetized with pentobarbital, and the hearts were rapidly excised and immediately mounted on an aortic cannula for retrograde perfusion (nonrecirculating) at a constant pressure of 55 mmHg. The buffer was composed of (in mM) 118 NaCl, 4.7 KCl, 24 NaHCO3, 1.2 KH2PO4, 1.2 MgSO4·7H2O, 11 glucose, and 2.5 CaCl2 anhydrous in distilled water at a pH of 7.4, and was continuously oxygenated with 95% O2-5% CO2. Care was taken to maintain both buffer temperature and heart temperature at 37°C. A balloon constructed of polyvinylchloride plastic film was inserted into the left ventricle (LV), inflated to an end-diastolic pressure of 5 mmHg, and used to monitor cardiodynamic function throughout the experiment.

After stabilization, all hearts underwent a 25-min intervention phase (Fig. 1). For each of the three cohorts, hearts were assigned to receive uninterrupted buffer perfusion (controls), brief PC ischemia, or exogenous administration of D-myo-Ins(1,4,5)P3 hexasodium (Calbiochem, La Jolla, CA). The PC stimulus consisted of two 5-min episodes of global ischemia interspersed with 5 min of reflow and followed by 10 min of reperfusion, while D-myo-Ins(1,4,5)P3 was dissolved in buffer and given over 1 min via a side port located immediately proximal to the heart at a final concentration (6 µM) shown previously to limit infarct size (9, 22, 23). In addition, to determine whether reduction of infarct size could be evoked by triggering a more distal signaling component common to both PC- and D-myo-Ins(1,4,5)P3-induced cardioprotection [in particular, opening of mitochondrial ATP-sensitive K+ (KATP) channels (8, 23, 29)] hearts in each cohort received 15 min of standard buffer perfusion followed by a 10 min infusion of diazoxide [Sigma, St. Louis, MO; final concentration in buffer: 100 µM (18)].


Figure 1
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  		Fig. 1. Schematic illustration of the protocol design. Hearts harvested from C57BL/6J, mutant Itpr-1opt+/–, and wild-type Itpr-1opt+/+, mice were assigned to control, preconditioned (PC), D-myo-inositol (1,4,5)trisphosphate [D-myo-Ins(1,4,5)P3]-, and diazoxide-treated groups.

 
After the 25-min intervention period, all hearts underwent 30 min of sustained global ischemia followed by 2 h of reperfusion (Fig. 1). The hearts were then cut into four to six transverse slices, and the extent of necrosis was delineated by triphenyltetrazolium staining (incubation for 15 min at 37°C). All hearts were digitally photographed, and infarct size was quantified in a blinded manner (without knowledge of the treatment group) by using image analysis software (SigmaScan Pro: Systat, Point Richmond, CA).

For each of the three cohorts, infarct size (expressed as a % of total LV weight) in control, PC, D-myo-Ins(1,4,5)P3-, and diazoxide-treated groups was compared by ANOVA, and, if significant F values were obtained, pairwise comparisons were made using the Student-Newman-Keuls test.


   RESULTS
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We confirmed that, as expected, mutant Itpr-1opt+/– mice displayed a ~50% deficit in Ins(1,4,5)P3 receptor-1 protein expression when compared with wild-type Itpr-1opt+/+ or C57BL/6J mice (Fig. 2). However, there were no differences in myocyte size, myocardial fibrosis, heart weight-to-body weight ratios, or baseline cardiodynamic performance (heart rate, LV developed pressure, dP/dt) among the three cohorts. In addition, LV function after relief of sustained global ischemia recovered to 30–40% of baseline values in all hearts, irrespective of the strain or the treatment group (data not shown).


Figure 2
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  		Fig. 2. Ins(1,4,5)P3 receptor-1 immunoreactivity in hearts from C57BL/6J, mutant Itpr-1opt+/–, and wild-type Itpr-1opt+/+ mice. Data are shown as means ± SE. *P < 0.05 vs. C57BL/6J.

 
For C57BL/6J mice, infarct size in control hearts averaged 53% of the total LV. Moreover, area of necrosis was, as expected, reduced to 30–34% of the LV in PC-, D-myo-Ins(1,4,5)P3-, and diazoxide-treated groups vs. controls (Figs. 3 and 4). Similar results [i.e., significant cardioprotection with PC, D-myo-Ins(1,4,5)P3, and diazoxide] were observed in hearts from wild-type Itpr-1opt+/+ mice (Fig. 4). In contrast, in the Itpr-1opt+/– cohort, only diazoxide-treated hearts displayed a significant reduction of infarct size when compared with matched controls: neither D-myo-Ins(1,4,5)P3 nor PC evoked an infarct-sparing effect in Ins(1,4,5)P3 receptor-1-mutant mice (Figs. 3 and 4). To rule out the concept that two 5-min episodes of PC ischemia may have constituted a subthreshold stimulus, two additional Ins(1,4,5)P3 receptor-1-mutant mice were enrolled in a post hoc manner and received four (rather than two) 5-min cycles of PC ischemia. The amplified PC stimulus was, similarly, ineffective in initiating protection: i.e., infarct size in these supplemental hearts averaged 63% of the total LV.


Figure 3
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  		Fig. 3. Original photographs of control, PC, D-myo-Ins(1,4,5)P3-, and diazoxide-treated hearts from C57BL/6J and mutant Itpr-1opt+/– mice. Hearts were cut into transverse slices and stained with triphenyltetrazolium chloride to distinguish necrotic (unstained) from viable (red) myocardium.

 

Figure 4
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  		Fig. 4. Infarct size [expressed as a % of the total left ventricle (LV)] in hearts from C57BL/6J, mutant Itpr-1opt+/– and wild-type Itpr-1opt+/+ mice assigned to control, PC, D-myo-Ins(1,4,5)P3-, and diazoxide-treated groups. Data are shown as means ± SE.

 

   DISCUSSION
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 MATERIALS AND METHODS
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The established, classical role of Ins(1,4,5)P3 lies in the control of calcium homeostasis (specifically, mobilizing the release of calcium from intracellular stores), initiated by binding of the second messenger to members of the Ins(1,4,5)P3 receptor family (3). However, in cardiomyocytes, in which ryanodine receptors serve as the primary calcium release channel for excitation-contraction coupling, the purpose of Ins(1,4,5)P3 is unclear (15, 27). Indeed, while the requisite components of Ins(1,4,5)P3 signaling [including Ins(1,4,5)P3 receptor-1, -2, and -3 subtypes] are present in the myocardium (10, 13, 20, 27), the role(s) of Ins(1,4,5)P3 signaling in the heart remain poorly defined. In this regard, the current results obtained in Itpr-1opt+/– mice provide novel evidence that Ins(1,4,5)P3 signaling contributes to the reduction of infarct size seen with ischemic PC.

Our data imply the specific involvement of the Ins(1,4,5)P3 receptor-1 subtype in the infarct-sparing effect initiated by both PC and exogenous D-myo-Ins(1,4,5)P3. These data are perhaps surprising, given the relative proportion and distribution of type-1 versus type-2 Ins(1,4,5)P3 receptors in the heart. In LV homogenates, the abundance of type-1 and type-2 receptors is approximately equal. However, in isolated cardiomyocytes, the predominant isoform is undoubtedly the type-2 Ins(1,4,5)P3 receptor, with neonatal myocytes purportedly expressing only the receptor-2 subtype (5, 7, 10, 15, 17, 20). This disparity between preparations may reflect an abundance of type-1 receptor on nonmyocytes (i.e., endothelial cells), a concept that is problematic as it is unclear how stimulation of Ins(1,4,5)P3 receptors on nonmyocytes would result in myocardial salvage. Expression of the receptor-1 subtype has, however, been detected in isolated adult cardiomyocytes by immunohistochemistry and in situ hybridization (5, 15, 17). Moreover, it is possible that low expression of type-1 Ins(1,4,5)P3 receptors in cardiomyocytes may be due in part to a loss of receptors, in particular, the population reportedly localized at intercalated discs (12), during dissociation and myocyte isolation. This concept, albeit speculative, may be noteworthy, as previous evidence from our group suggests that cardioprotection achieved with D-myo-Ins(1,4,5)P3 is triggered via stimulation of Ins(1,4,5)P3 receptors localized in proximity to gap junctions/hemichannels (22).

A second intriguing aspect of this study is that, in heterozygous Ins(1,4,5)P3 receptor-1-mutant mice displaying a partial deficit in Ins(1,4,5)P3 receptor-1 protein, there was no evidence of partial, intermediate, or incomplete cardioprotection with PC. Rather, infarct sizes in hearts that received PC ischemia were comparable to those seen in matched controls. This concept is not without precedent: similar results (that is, a complete failure of PC to limit infarct size) has been observed in heterozygous mice exhibiting a 50% deficiency in the gap junction protein, connexin 43 (24, 25). We cannot, however, speculate on the minimum threshold deficit in Ins(1,4,5)P3 receptor protein-1 expression that results in a total loss of infarct size reduction with PC.

The current data showing an absence of PC-induced cardioprotection in Itpr-1opt+/– mutants suggest that the Ins(1,4,5)P3 receptor-1 subtype is an integral component of (i.e., in series with, rather than in parallel with or alternative to) the signaling pathway responsible for PC. However, it is unclear whether the inability of PC [and exogenous D-myo-Ins(1,4,5)P3] to trigger protection in the mutant cohort is due entirely to the deficit in Ins(1,4,5)P3 receptor-1 protein or whether Itpr-1opt+/– mice may display more global (and as-yet uncharacterized) defects in cardioprotective signaling. Although definitive resolution of this issue is beyond the scope of the current study, two potentially confounding possibilities were explored. First, we prospectively focused on a signaling element common to both PC- and D-myo-Ins(1,4,5)P3-induced cardioprotection (23): specifically, opening of mitochondrial KATP channels via the putative agonist, diazoxide. We found that preischemic infusion of diazoxide significantly reduced infarct size in all three strains of mice, including the Itpr-1opt+/– cohort. Second, the reported involvement of gap junctions in PC-induced cardioprotection (14, 24, 25), together with the aforementioned concept that Ins(1,4,5)P3 receptors located at intercalated discs contribute to the infarct-sparing effect of D-myo-Ins(1,4,5)P3 (22), raise the question of whether the inability of PC or D-myo-Ins(1,4,5)P3 to limit infarct size in mutant Itpr-1opt+/– mice is simply explained by an accompanying deficit in gap junction protein. We addressed this issue in a post hoc manner by standard immunoblotting and found no evidence of a deficiency in connexin 43 protein expression in Itpr-1opt+/– mutants vs. either wild types or C57BL/6J mice. Thus, although we cannot speculate on the efficacy of adenosine, bradykinin, opioid receptor agonists, or the host of other "PC-mimetic" agents that have been described (21, 29), these results demonstrate that at least some cardioprotective signaling elements remain intact and responsive in Ins(1,4,5)P3 receptor-1 mutant mice.

Among the host of additional questions raised by these data, perhaps the most compelling issue is: where, precisely, does the Ins(1,4,5)P3 receptor fit into the cardioprotective signaling paradigm? We cannot postulate, on the basis of the current study, whether the contribution of Ins(1,4,5)P3 lies in its classic role as a regulator of calcium homeostasis, or whether, in the setting of ischemia-reperfusion, the receptor functions in its as-yet poorly understood role as a signaling molecule or scaffolding protein (11, 19, 28). Moreover, the current data obtained in mutant mice does not allow us to discern whether the Ins(1,4,5)P3 component of PC-induced cardioprotection is manifest before ischemia, during ischemia, or at the time of reflow. Finally, although the infarct-sparing effect of D-myo-Ins(1,4,5)P3 has been well-documented in rabbit hearts (9, 22, 23), it remains to be established whether the current findings can be extrapolated to other species. Nonetheless, our results obtained in Itpr-1opt+/– mutants reveal that Ins(1,4,5)P3 signaling plays a role in the reduction of infarct size achieved with ischemic PC in the mouse model.


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This study was supported by National Heart, Lung, and Blood Institute R01-HL-63713 to K. Przyklenk.


   ACKNOWLEDGMENTS
 
This study was presented in part as a Late-Breaking Abstract at the Annual Scientific Sessions of the American Heart Association, Dallas, TX, November 2005.


   FOOTNOTES
 

Address for reprint requests and other correspondence: K. Przyklenk, Dept. of Emergency Medicine, Univ. of Massachusetts Medical School, 55 Lake Ave. North, Worcester, MA 01655 (e-mail: karin.przyklenk{at}umassmed.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


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