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knockout mouse
hearts
1 Cardiology Section, Veterans Affairs Medical Center, San Francisco, 94121; 2 Department of Molecular Pharmacology, Stanford University, Stanford 94305; 3 Ernest Gallo Clinic and Research Center, University of California, San Francisco 94608; and 4 Immunology Division, Department of Medicine, University of California, San Francisco, San Francisco, California 94143
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Sphingosine-1-phosphate (S1P)
protects neonatal rat cardiac myocytes from hypoxic damage through
unknown signaling pathways. We tested the hypothesis that S1P-induced
cardioprotection requires activation by the 
-isoform of protein
kinase C (PKC) by subjecting hearts isolated from PKC knockout
mice and wild-type mice to 20 min of global ischemia and 30 min
of reperfusion. Pretreatment with a 2-min infusion of 10 nM S1P
improved recovery of left ventricular developed pressure (LVDP) in both
wild-type and PKC knockout hearts and reduced the rise in LV
end-diastolic pressure (LVEDP) and creatine kinase (CK) release.
Pretreatment for 2 min with 10 nM of the ganglioside GM-1 also improved
recovery of LVDP and suppressed CK release in wild-type hearts but not
in PKC knockout hearts. Importantly, GM-1 but not S1P, increased the
proportion of PKC localized to particulate fractions. Our results
suggest that GM-1, which enhances endogenous S1P production, reduces
cardiac injury through PKC-dependent intracellular pathways. In
contrast, extracellular S1P induces equivalent cardioprotection through PKC-independent signaling pathways.
ischemia-reperfusion injury; -isoform of protein kinase
C
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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SPHINGOSINE-1-PHOSPHATE (S1P) is a lysophospholipid growth factor and mediator of diverse cellular functions, which transmits signals to cells by autocrine and paracrine mechanisms (24). It is generated from sphingomyelin and other phospholipid precursors that are stored in membranes and is secreted by cardiac myocytes, platelets, macrophages, and epithelial cells to produce up to micromolar concentrations in normal serum (24). S1P binds to G protein-coupled cell surface receptors formerly termed endothelial differentiation gene (EDG) receptors (12), now called S1P receptors. The high level of expression of the EDG 1 (S1P1), EDG 3 (S1P3), and EDG 5 (S1P2) receptor mRNAs in mouse heart (31) and the essential role of the S1P1 receptor in heart development (17) raise the possibility that this lipid mediator could alter cardiac function under some physiological and/or pathological conditions, such as ischemia. S1P is well recognized as a survival factor in a number of native cell types and cell lines (7). Gangliosides are a class of sialic acid-containing glycosphingolipids associated with the plasma membrane, and the ganglioside GM-1, which stimulates generation of S1P, also acts as a survival factor (4). In a recent study, Karliner et al. (14) showed in cultured neonatal rat cardiac myocytes that pretreatment with S1P or GM-1 reduced hypoxic cell death. This cardioprotection was abolished by the putative nonselective protein kinase C (PKC) inhibitor chelerythyrine (14).
There is abundant evidence that activation of the -isoform of PKC
(PKC) is required for cardioprotection induced by brief bouts of
ischemia or hypoxia or by pharmacological agents. PKC is
activated by peconditioning (23, 25), and a selective
peptide inhibitor of PKC blocks this cardioprotection
(11). Furthermore, expression of a selective peptide
activator of PKC in the heart of transgenic mice increases
cardioprotection (8). Because Karliner et al.
(14) found that S1P provides protection from hypoxic
damage in culture, we set out to determine whether such protection can
be induced in the isolated beating heart. We also wanted to learn
whether PKC mediates these cardioprotective effects, and to this end
we used PKC knockout mice.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals.
Mutant mice lacking PKC were originally derived using homologous
recombination in embryonic stem cells with a neomycin gene insert to
disrupt the first coding exon of the PKC gene (15). The
resulting chimeric mice were crossed with C57B16/J mice to test for
germ line transmission of the mutation. Chimeras were then crossed with
129SvJae mice to establish an inbred 129SvJae line harboring the
null mutation. Male PKC (+/
) heterozygous 129SvJae mice were
crossed with C57BL/6J female mice to yield F1 generation hybrid
C57B1/6J x129SvJae heterozygous progeny, which were intercrossed
to generate F2 generation wild-type and PKC null male mice for the
study. Homozygous male knockout mice bred from these animals are of
normal body weight and lifespan compared with wild-type mice and cannot
be distinguished from littermates in the normal cage environment.
Genotyping using PCR to confirm the absence of PKC DNA was routinely
performed on tail samples. Only male wild-type mice and PKC knockout
mice were used in the present study.
Langendorff isolated perfused heart preparation. Mice were heparinized (500 U/kg ip) and anesthetized with pentobarbital sodium (60 mg/kg ip). Hearts were rapidly excised, washed in ice-cold arresting solution (120 mmol/l NaCl, 30 mmol/l KCl), and cannulated via the aorta on a 20-gauge stainless steel blunt needle. Hearts were perfused at 70 mmHg on a modified Langendorff apparatus using Krebs-Henseleit solution containing (in mmol/l) 118 NaCl, 4.7 KCl, 2.5 CaCl2, 1.2 MgSO4, 1.2 KH2PO4, 24 NaHCO3, 5.5 glucose, 5.0 Na pyruvate, 0.5 EDTA, and bubbled with 95% O2-5% CO2 at 37°C. Platinum electrodes connected to a Grass Instrument stimulus generator were used to pace hearts at 360 beats/min.
Ischemia-reperfusion experimental protocol. Hearts were perfused continuously with oxygenated Krebs-Henseleit solution for 70 min to establish the stability of the preparation. Subsequently, separate ischemia-reperfusion studies were carried out as follows: baseline left ventricular (LV) developed pressure (LVDP), LV end-diastolic pressure (LVEDP), and coronary flow (CF) were measured after a 20-min equilibration period. All hearts were then treated with vehicle or agonist for 2 min, which was then washed out for 5 min. The hearts were then subjected to 20 min of global ischemia, which was achieved by turning a stopcock just proximal to the aortic cannula to completely halt coronary perfusion. During global ischemia, pacing was temporarily stopped, and cardiac temperature was maintained at 37°C in a humidified chamber. All hearts were then reperfused with Krebs-Henseleit solution for 30 min. Hemodynamics were recorded continuously and measured every 5 min during reperfusion.
Measurement of LV performance.
LVDP (LVDP = LV systolic pressure LVEDP) was measured
using a 1.4-Fr micromanometer (Millar Instruments) passed into a
polyvinylchloride film balloon filled with water to set the LVEDP at
<10 mmHg. The balloon was inserted through the left atrium into the
left ventricle, and pressures were recorded continuously on a Gould TA
240 chart recorder. CF was measured by collecting effluent from the
coronary sinus.
Measurement of creatine kinase release. Coronary effluent was collected every 5 min during the reperfusion period. Creatine kinase (CK) release was measured using a commercially available kit (Sigma). Values were corrected for CF rate and wet heart weight.
Tissue sample preparation for Western blot.
After 20 min of stabilization, isolated mouse hearts were perfused with
10 nM GM-1 or S1P for 2 min, followed by a 5-min washout period. These
pretreated hearts were immediately put into liquid nitrogen and stored
at 80°C. Frozen myocardial ventricular tissue samples were minced.
Total cellular proteins were prepared by homogenization of the minced
tissue (Brinkman Polytron PT 3000) in sample buffer containing 10 mM
Tris · HCl (pH 7.4), 1 mM EDTA, 1 mM EGTA, 0.25 M sucrose, 25 µg/ml aprotinin, 25 µg/ml leupeptin, 20 µg/ml soybean trypsin
inhibitor, and 17 µg/ml phenylmethylsulfonyl fluoride. The cytosolic
and particulate portions of total cellular proteins were separated by a
30-min centrifugation at 47,000 g (25). After
dilution, protein concentration was determined by bovine serum albumin
as a standard according to the method of Bradford (Bio-Rad
Laboratories; Hercules, CA). The yields of total cellular proteins,
cytosolic proteins, and particulate proteins were recorded for each
tissue sample tested.
PKC Western blot.
Assessment of PKC isozymes was conducted using standard SDS-PAGE
Western blot techniques. Briefly, 50 µg of protein derived from the
cytosolic fraction or the particulate fraction of the homogenate was
electrophoresed on a 7.5% denaturing gel at 30 mA per lane for
1-2 h. Proteins were electrotransferred onto a nitrocellulose
membrane (Bio-Rad) at 200 mA for 2 h. Adequate background blocking
was accomplished by incubating the nitrocellulose membrane with 5%
nonfat dry milk in phosphate buffer solution (pH 7.4). Antibodies
against PKC isozymes 
, , and 
(Transduction Laboratories;
Lexington, KY) were used to measure the expression of individual PKC
isozymes. PKC immunoreactive bands were quantitated by densitometric
analysis of digitized autoradiograms with NIH Image 1.61 software.
Infarct size determination with triphenyltetrazolium chloride
staining.
After 20 min of global ischemia and 30 min of reperfusion, a
subset of hearts in each group was infused with 15 ml of 1%
triphenyltetrazolium chloride (Sigma) in phosphate-buffered saline at a
rate of 1.5 ml/min. Hearts were then removed from the cannula, weighed,
and fixed overnight in 10% formalin, after which they were removed from formalin and stored frozen at 20°C until sectioning for analysis of LV infarct size. Hearts were sliced into 2-mm transverse sections from apex to base and digitally photographed on each side
(Camedia E-10, Olympus Camera). Computerized area analysis was
performed with National Institutes of Health Image software. The
infarct size of each section was expressed as a fraction of the area at
risk defined as the total area of the left ventricle in this global
ischemia model.
Statistical analysis. Results are reported as means ± SE. Comparisons between groups were made using repeated- measures or one-way analysis of variance, followed by post hoc testing (Newman-Keuls). P < 0.05 was considered statistically significant.
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Baseline functional measurements in wild-type hearts.
There were no significant baseline differences in hemodynamic
measurements among hearts from wild-type or PKC knockout mice (Table
1). After pretreatment before
ischemia-reperfusion with either exogenous S1P or GM-1, which
elicits generation of endogenous S1P (4), these values
remained unchanged among groups and in comparison with baseline values
(Table 2).
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S1P and GM-1 reduce myocardial reperfusion injury.
Hearts were suspended in the Langendorff apparatus and treated with a
2-min infusion of either 10 nmol/l S1P or 10 nmol/l GM-1 at the end of
a 20-min equilibration period as described under methods. Hearts were
then subjected to 20 min of global ischemia and 30 min of
reperfusion. As can be seen in Fig. 1, both S1P and GM-1 markedly improved LV systolic function
throughout reperfusion as measured by LVDP and maximal rate of LV
pressure development over time
(+dP/dtmax). Cardiac diastolic
function (LVDP and dP/dtmax) were also
improved after S1P and GM-1 pretreatment (Fig.
2). CF exceeded control values in both
the S1P group and the GM-1 group (Fig.
3). These interventions also
reduced myocardial injury as measured by decreases in CK release (Fig.
4). As shown in Fig.
5, infarct size was also reduced in
both the S1P- and GM-1-pretreated groups compared with control.
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Effects of S1P and GM-1 on PKC translocation in wild-type mouse
hearts.
Because the nonselective PKC inhibitor chelerythrine abolished S1P and
GM-1 cardioprotection in cultured neonatal rat cardiac myocytes
(14), we wondered whether the ability to induce
cardioprotection was isozyme specific. Hearts from wild-type mice were
treated with 10 nmol/l S1P or 10 nmol/l GM-1 or vehicle for 2 min in
the Langendorff apparatus and then homogenized. Western blot analysis was then performed as described in METHODS. As can be seen
in Fig. 6, GM-1, but not S1P, caused
translocation of PKC, but not PKC or PKC, in wild-type mouse
hearts. This observation suggested that GM-1 requires PKC
translocation for cardioprotection, but that S1P might not act through
PKC. To test this hypothesis, we examined the cardioprotective
effect of S1P and GM-1 in mice that lack PKC.
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Do S1P and GM-1 reduce myocardial ischemic injury in PKC
knockout mice?
At baseline and immediately after infusion of S1P and GM-1, there were
no differences in hemodynamic measurements and CF between PKC
knockout mice and wild-type mice (Tables 1 and 2). We reasoned that
pretreatment with GM-1 would not be cardioprotective in the PKC
knockout mouse if translocation of PKC is an absolute requirement for reducing ischemia-reperfusion injury. As shown in Fig.
7, GM-1 did not protect ischemic
myocardium in PKC knockout mice as evidenced by the absence of
improvement in LVDP and CK release during reperfusion. In contrast,
S1P, which did not induce PKC translocation (Fig. 6), reduced
ischemia-reperfusion injury. LVDP was improved and CK release
was reduced in the S1P group (Figs. 7 and
8), consistent with an PKC-independent
mechanism of action.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The major finding of this study is that both S1P and GM-1 protect
the isolated buffer-perfused mouse heart against
ischemia-reperfusion injury. These observations are the first
to show in any whole organ that S1P reduces damage due to
ischemia-reperfusion. Using PKC knockout mice, we also found
that S1P given exogenously does not require PKC for its
cardioprotective action. In contrast, the ganglioside GM-1, which
increases intracellular S1P levels by stimulating sphingosine kinase
activity (4), has an absolute requirement for PKC. This
PKC dependence may be for S1P production or intracellular signaling,
or both. These findings are consistent with experiments showing that
GM-1, but not S1P, translocates PKC but not PKC or PKC, which
indicates PKC engagement in intracellular S1P generation and/or signaling.
S1P and protection from cell death. All prior studies of S1P as a survival factor have relied on in vitro data in cell lines and have focused on apoptosis as the sole model of cell death. From such studies, Spiegel and colleagues developed a model describing an intracellular ceramide-S1P "rheostat" (7, 16). This model is founded on observations that increases in the concentration of the proapoptotic molecule ceramide can be countered by increases in the intracellular levels of S1P (7). Thus inhibition of sphingosine kinase (the final step in S1P synthesis) induces cell death, whereas activation of sphingosine kinase by PKC increases intracellular S1P and enhances cell survival (7, 16). Overexpression of sphingosine kinase in cell lines also protects against apoptosis induced by serum deprivation or ceramide elevation (22). In addition, the ganglioside GM-1 stimulates synthesis of S1P by activating sphingosine kinase and protects cultured rat heart fibroblasts from ceramide-induced apoptosis (4). In cultured neonatal rat ventricular myocytes, Karliner et al. (14) have previously shown that both S1P and GM-1 reduce hypoxic cell death and prevent cell death due to inhibition of sphingosine kinase under normoxic conditions.
There is also evidence that S1P acts extracellularly to enhance cell survival via activation of EDG (S1P) receptors, particularly S1P3 and S1P2 (1). Goetzl and colleagues (9) demonstrated that exogenous S1P inhibits ceramide-induced apoptosis via the S1P3 receptor in human lymphoblastoma cells by suppressing cellular levels of the apoptosis-promoting protein Bax without alteration in levels of Bcl-xL or Bcl-2. Transfection of plasmids encoding transcripts antisense to the S1P3 receptor inhibited S1P-induced reduction of Bax expression and protection against apoptosis. Recently, An et al. (1) reported that S1P3 and S1P2 receptors mediate protection against apoptosis induced by serum starvation in HTC4 hepatoma cells. In prior work, Goetzl et al. (10) have shown that cultured cardiac myocytes express S1P3 and S1P2 receptors. From the cardioprotective action of S1P and GM-1 in cultured neonatal rat cardiac myocytes, we wondered whether such protection would occur in an isolated organ system. Our findings indicate that a short (2 min) exposure to a low concentration (10 nM) of either S1P or GM-1 reduced ischemia-reperfusion injury as evidenced by increased LVDP, decreased LVEDP, reduced CK release and infarct size. In cultured neonatal rat ventricular myocytes, much higher concentrations (10 µM) of these agents for a much longer time (2 h) were used to achieve cardioprotection (14). Although we did not directly explore the mechanism of cell death in the present study, the relatively short time of ischemia-reperfusion (total of 50 min), which leads to extensive CK release, as well as to massive necrosis in the control state, would seem to exclude apoptosis as an important mode of cell death. In this connection, it should be noted that a large infarct area resulted from a relatively short ischemic time of 20 min and reperfusion time of 30 min. In an identical model using a different a strain of mouse, Tekin et al. (28) recently reported that after 20 min of ischemia and 30 min of reperfusion, infarct size ranged between 30 and 38%. Our infarct size results in the control group are virtually identical to those of Tekin et al. Infusion of 10 nM S1P or 10 nM GM-1 for 2 min via the aortic cannula in the isolated Langendorff buffer-perfused mouse heart preparation resulted in no significant changes in coronary flow, LVDP, or LVEDP. In preliminary studies, we found that 100 nM S1P but not 100 nM GM-1 caused apparent coronary vasoconstriction and decreased LVDP (data not shown). Others have reported related hemodynamic changes after administration of S1P. In a canine isolated, blood-perfused sinoatrial node and papillary muscle preparation, Sugiyama et al. (27) observed that 10 µg of S1P given over 4 s directly into a nutrient coronary artery caused sinus tachycardia and coronary vasoconstriction followed by a weak negative inotropic effect. In contrast, the same group noted in an in vivo rat model that intravenous injection of S1P decreased heart rate, ventricular contraction, and blood pressure (26). Bischoff et al. (2) reported that intravenous injection of S1P rapidly (within 30 s), transiently and dose dependently reduced rat renal blood flow and mesenteric blood flow without affecting mean arterial pressure or heart rate. Thus species difference, mode of administration, and drug concentration will be important considerations in understanding the role of S1P or GM-1 in future studies of myocardial protection and preservation.PKC, PKC knockout mice, and sphingosine kinase.
PKC is a family of isozymes that translocate between subcellular
compartments upon activation (20). It is likely that
following activation, these isozymes are bound to selective anchoring
proteins or internal receptors for activated C-kinase (RACKs). There is abundant evidence that activated PKC translocates to its RACK during
acute ischemia and pharmacological preconditioning
(18). Isozyme-selective agonists and antagonists of PKC
translocation and function have been developed (5, 8, 11,
13). Previously, we employed an PKC peptide antagonist to
demonstrate that PKC mediates hypoxic preconditioning of cultured
neonatal rat cardiomyocytes (11) and pharmacological
preconditioning of neonatal mouse cardiac myocytes (13).
Activation of particular PKC isozymes, such as PKC or PKC,
appears to have opposing actions on protection from ischemia-induced damage, with activation of PKC being
cardioprotective, whereas activation of PKC increases damage induced
by ischemia in vitro and in vivo (5).
. This led us to ask whether it would be possible to confirm the
role of PKC in this model of cardioprotection by using the PKC
knockout mouse. This mouse has been previously used for neurological
studies that demonstrate altered nocioception (15) and
supersensitivity to the sedative effects of ethanol, barbiturates, and
benzodiazepines (21). The homozygous male mice used in our
studies are of normal body weight and lifespan compared with their
wild-type littermates and are indistinguishable from the latter in the
normal cage environment. Their LV function and CF rates in the control
state are identical to wild-type mice.
Results of the experiments in the PKC knockout mice were consistent
with observations of PKC translocation using Western blotting. GM-1,
which translocated PKC in wild-type mouse hearts, was ineffective in
protecting PKC null mouse hearts from ischemia-reperfusion damage. Conversely, S1P, which did not translocate PKC in wild-type hearts, was still cardioprotective in PKC null mouse hearts. These
observations are consistent with a requirement of PKC for the
generation of intracellular S1P via activation of sphingosine kinase
(3, 7, 16). These data also suggest that in the heart
exogenously administered S1P acts through cognate receptors via yet to
be defined PKC-independent pathways that are currently under study in
our laboratory.
Previously we found that a putative PKC inhibitor chelerylthrine
blocked the protective effect of S1P in neonatal rat cardiac myocytes (14). Recently, Yamamoto et al. (29)
reported that chelerythrine induces apoptosis through
generation of reactive oxygen species in neonatal rat cardiac myocytes.
As pointed out by Clerk (6), PKC inhibitors may act
independent of any effect on PKC. Thus, chelerythrine, which has been
widely used as a PKC inhibitor, may act through another mechanism, and
this may explain the apparent discrepancy between our current study and
the prior in vitro result (14) with respect to the
relation between PKC and S1P.
In summary, we have shown that both exogenous S1P and GM-1, a compound
that activates sphingosine kinase and is known to increase endogenous
S1P levels (4), protect the ex vivo heart from
ischemia-reperfusion injury. GM-1 requires PKC for its
cardioprotective action. As S1P is released by cardiac myocytes, as
well as by platelets and macrophages (30), its
enhancement, whether intracellular or extracellular, represents a novel
model of cardioprotection that deserves further exploration.
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ACKNOWLEDGEMENTS |
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This study was supported by a Merit Review Grant from the Research Service of the Department of Veterans Affairs (to J. S. Karliner), by RO1 HL-31809 (to E. J. Goetzl), and RO1 HL-52141 (to D. Mochly-Rosen) from the National Institutes of Health. M. O. Gray is the recipient of a Research Career Development Award from the Department of Veterans Affairs Research Service.
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FOOTNOTES |
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Address for reprint requests and other correspondence: J. S. Karliner, Cardiology Section (111C), 4150 Clement St., San Francisco, CA 94121 (E-mail: Joel.Karliner{at}med.va.gov).
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.
First published February 14, 2002;10.1152/ajpheart.01029.2001
Received 27 November 2001; accepted in final form 12 February 2002.
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TOP
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METHODS
RESULTS
DISCUSSION
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, Individual mice;
, means ± SE for respective group.
*P < 0.05, compared with control group.
n = 4 hearts for each group.
