Published online before print April 10, 2008, doi: 10.1161/CIRCRESAHA.107.167544
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© 2008 American Heart Association, Inc.
Cellular Biology |
S100A8 and S100A9 Mediate Endotoxin-Induced Cardiomyocyte Dysfunction via the Receptor for Advanced Glycation End Products
From the Critical Care Research Laboratories, St. Paul’s Hospital, University of British Columbia, Vancouver, Canada.
Correspondence to John H. Boyd, MD, Critical Care Research Laboratories, 1081 Burrard St, Vancouver, BC, Canada V6Z 1Y6. E-mail jboyd{at}mrl.ubc.ca
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Abstract |
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Cardiovascular dysfunction as a result of sepsis is the leading cause of death in the critically ill. Cardiomyocytes respond to infectious pathogens with a Toll-like receptor–initiated proinflammatory response in conjunction with a decrease in contractility, although the downstream events linking Toll-like receptor activation and reduced cardiac contractility remain to be elucidated. Using microarray analysis of cardiac tissue exposed to systemic lipopolysaccharide (LPS), we discovered that 2 small calcium-regulating proteins (S100A8 and S100A9) are highly upregulated. HL-1 cardiomyocytes, isolated primary cardiomyocytes, and live mice were exposed to LPS, whereas beating HL-1 cells had S100A8 and S100A9 overexpressed and their calcium flux quantified. Using in vivo microbubble technology, we delivered S100A8 and S100A9 to normal mouse hearts; using the same technology, we inhibited S100A9 production in mouse hearts and subsequently exposed them to LPS. Coimmunoprecipitation of S100A8 and S100A9 identified interaction with RAGE (the receptor for advanced glycation end products), the cardiac function and postreceptor signaling of which were investigated. HL-1 cardiomyocytes, isolated primary cardiomyocytes, and whole hearts exposed to LPS have large increases in S100A8 and S100A9. Cardiac overexpression of S100A8 and S100A9 led to a RAGE-dependent decrease in calcium flux and, in the intact mouse, to a decreased cardiac ejection fraction, whereas knockdown of S100A9 attenuated LPS-induced cardiac dysfunction. Cardiomyocytes exposed to LPS express S100A8 and S100A9, leading to a RAGE-mediated decrease in cardiomyocyte contractility. This finding provides a novel mechanistic link between circulating pathogen-associated molecular products and subsequent cardiac dysfunction.
Key Words: S100 proteins • RAGE • ventricular contractility
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Introduction |
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Sepsis causes myocardial dysfunction, which contributes to hypotension, impaired perfusion, and even death.1 The precise mechanisms linking sepsis to myocardial dysfunction are still unclear; however, it is known that the function of cardiomyocytes extends beyond contraction to provide the motive force driving cardiac output and arterial pressure generation. There is increasing evidence that cardiomyocytes have additional properties, analogous in some respects to innate immune antigen-presenting cells that allow cardiomyocytes to respond to "danger" signals with an innate immune inflammatory and functional response.2–23 We have recently shown that cardiomyocytes express multiple Toll-like receptors (TLRs) that signal predominantly through NF-
B when stimulated by pathogenic molecules, resulting in decreased cardiomyocyte contractility.24 However, the downstream elements that link TLRs and cardiomyocyte contractility remain unknown. Because decreased contractility can be observed in isolated cardiomyocytes, we searched for candidate molecules that are highly regulated by exposure to TLR ligands and are capable of either exerting an autocrine effect and/or interacting with key intracellular contractile proteins. Using microarray analysis of cardiac tissue following systemic challenge with the TLR ligand lipopolysaccharide (LPS), we identified 2 small calcium-binding proteins (S100A8 and S100A9) as being highly upregulated in cardiomyocytes as early as 6 hours after LPS exposure. S100A8 and S100A9 are members of the EF-hand family of proteins, in which the S100 proteins comprises the largest subfamily. S100 proteins are known to be important to heart function: S100A1 is a key mediator of contractile performance and overexpression of myocardial S100A1 leads to increased contractility25 and improved performance after myocardial infarction,26 whereas S100 A1 knockout mice exhibit features of congestive heart failure.27 S100A1 exerts its positive effect on calcium flux and contractility via interaction with and potentiation of sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) and the ryanodine receptor (RyR)2.25–35 Although S100A1 has been identified as an important therapeutic target, to date, there is little information about members of the S100 family being functionally present in the heart during inflammation or sepsis.
Unique among EF-hand proteins, S100A8 and S100A9 are found in both the intracellular and extracellular spaces36–38 and, therefore, could potentially act both within the cell and in an autocrine manner. In immune cells, S100A8 and S100A9 are known to be upregulated and secreted in inflammatory conditions,36–40 leading to signaling via RAGE (receptor for advanced glycation end products) to induce chemotaxis of neutrophils and amplify the proinflammatory cascade.41 In addition to this outside-in signaling, given the high degree of homology between the members of the S100 family,42 it is possible that S100A8 and S100A9 interact with 1 or more of the calcium-regulating proteins SERCA2a and RyR2 to exert an intracellular effect on cardiomyocyte contractility.
We, therefore, hypothesized that cardiomyocytes produce S100A8 and S100A9 in response to exposure to LPS. Given their dual intra- and extracellular roles, we also hypothesized that there would be separate extracellular (RAGE-dependent) and intracellular (RAGE-independent) effects on cardiac contractility.
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Materials and Methods |
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Cell Line
HL-1 cells are an immortalized cell line with adult cardiac morphological, biochemical, and electrophysiological properties, including contraction and biochemical response to cognate ligands.43 Stimulations and transfections were performed with the cells at confluence.
Primary Murine Cardiomyocytes
Murine ventricular myocytes were isolated from 10- to 14-week-old adult male mice. Isolation was performed as previously described.24
Cardiac-Specific Gene Delivery
We altered previously published methods of ultrasound guided gene therapy44–49 using commercially available reagents and confirming cardiac delivery in preliminary experiments using LacZ as a marker.
Echocardiographic Assessment of Mice
Mice were lightly anesthetized with 1% to 3% inhaled isoflurane and placed on a warming blanket. M-mode echocardiograms were targeted from 2D echoes obtained using the Vevo 770 ECHO (Visualsonics, Toronto, Ontario, Canada) operating at a 120-Hz frame rate.
Statistical Analysis
All values were expressed as means±SE. For each experimental condition and time point, 4 independent replicate analyses were performed, unless otherwise noted. ANOVA and the post hoc Bonferroni test were used to identify specific differences between groups. The analyses were performed using Sigmastat (SPSS, Chicago, Ill), and statistical significance was set at P<0.05.
An expanded Materials and Methods section is available in the online data supplement at http://circres.ahajournals.org.
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Results |
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Systemic Treatment With LPS Results in Reduced Cardiac Ejection Fraction and Is Associated With a Large Increase in Left Ventricular S100A8 and S100A9
Adult male mice were injected IP with 40 mg/kg Escherichia coli–derived LPS, and cardiac function was assessed preinjection (baseline) and at 6 hours after LPS by echocardiography. Baseline cardiac ejection fraction was 76%, falling to 29% 6 hours following injection of LPS (Figure 1A). Left ventricular tissue was harvested immediately following echocardiography at 6 hours, and quantitative RT-PCR revealed a 42-fold increase in S100A8 and a 49-fold increase in S100A9 mRNA compared with saline-treated mice (Figure 1B).
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S100A8 and S100A9 Are Constitutively Found in the HL-1 Cardiac Cell Line, Primary Cardiomyocytes, and Cardiac Tissue; Both Proteins Are Upregulated Following Exposure to LPS
To confirm that cardiomyocytes, rather than nonmyocyte cardiac cells, were responsible for cardiac S100A8 and S100A9 production, immunoblotting was performed on protein lysates from HL-1 cardiomyocytes, primary isolated cardiomyocytes, and left ventricular cardiac tissue exposed to either saline or LPS. All 3 groups had low levels of S100A8 and S100A9 constitutively expressed (saline-treated), whereas exposure to LPS resulted in increased S100A8 and S100A9 expression in all 3 groups (Figure 2).
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Production of S100A8 and S100A9 in Cardiomyocytes Exposed to LPS Is Dependent on MyD88 and Partially Dependent on NF-B
To determine the pathways responsible for LPS-induced production of S100A8 and S100A9, we used genetically altered mice deficient in the major pathways downstream from TLRs. Because TLR signaling is generally divided into MyD88-dependent or MyD88-independent, we chose to examine whether this adaptor protein was necessary for S100 protein production. In wild-type mice, LPS treatment resulted in a large increase in cardiac S100A8 and S100A9 production, whereas MyD88-null mice had no detectable production of either protein (Figure 3A and 3B). NF-B is among the major downstream targets of MyD88, and is the predominant pathway in early inflammatory signaling. We found that NF-B–deficient mice had increased S100A8/A9 production in response to LPS; however, this increase was significantly attenuated when compared with the response observed in wild-type mice (Figure 3A and 3B).
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S100A8 and S100A9 Both Result in Decreased Cardiomyocyte Calcium Flux
HL-1 cells beat spontaneously in a concentric fashion, and, therefore, usual measures of contractility, such as fractional shortening, are not able to be reliably performed. However, it is well documented that the HL-1 cardiac action potential, as measured by either patch-clamp or calcium-gated fluorescence, mirrors the expected cardiac contractile response when exposed to cognate cardiac ligands.50 We assessed the effect of S100A8 and S100A9 on cardiac contractility by measuring calcium flux in HL-1 cells transfected with plasmids encoding cDNA from 1 or both and compared these cells to those transfected with a control plasmid (LacZ). S100A8, S100A9, and both together resulted in a significant decrease in calcium flux compared with control vector (Figure 4A and 4B).
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Cardiac Delivery of S100A8 and S100A9 In Vivo Results in Decreased Ejection Fraction; Knockdown of S100A9 Abrogates LPS-Induced Cardiac Dysfunction
We used small animal echocardiography combined with lipid microbubbles carrying endotoxin-free plasmids to deliver S100A8 and S100A9 or both to the murine heart in vivo. As demonstrated in Figure 5A through 5C, by day 2, there was a strong trend toward decreased cardiac contractility in mice given cardiac S100A8, S100A9, or both compared with control plasmid, although only S100A9 reached statistical significance. All 3 groups demonstrated significant decreases in cardiac ejection fraction compared with control plasmid by day 5.
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In separate mice, we determined whether S100A9 has a role in LPS-induced cardiac dysfunction. One week before LPS injection, cardiac-specific delivery of S100A9 small interfering (si)RNA was performed, and ejection fraction was measured before and 6 hours after LPS (Figure 5D). Mice that had received control plasmid had a 35% reduction in cardiac ejection fraction compared with a 12% reduction in mice in which S100A9 production in response to LPS was reduced by half (Figure 5D).
Coimmunoprecipitation Reveals a Physical Interaction Between RAGE and Cardiac S100A8 and S100A9
Because S100A8 and S100A9 are secreted and interact with the RAGE receptor in other cell types, we next determined whether cardiac S100A8 or S100A9 interacted with the cardiac RAGE receptor. C57BL/6 mice were injected IP with 40 mg/kg LPS to upregulate S100A8 and S100A9. Six hours after injection, hearts were excised and digested to obtain isolated cardiac myocytes. Coimmunoprecipitation was performed with anti-S100A8, anti-S100A9, or nonspecific IgG, and the immunoprecipitate was then probed with anti-RAGE antibody. We found that RAGE coimmunoprecipitated with both S100A8 and S100A9, demonstrating a strong interaction between the RAGE receptor and these proteins (Figure 6).
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S100A8 and S100A9 Decrease Cardiomyocyte Calcium Flux and Induce NF-B via the Transmembrane RAGE Receptor
Given that S100A8 and S100A9 physically interact with RAGE on cardiomyocytes (Figure 6), we next determined whether this interaction was responsible for the decrease in cardiac contractility. Anti-RAGE blocking antibody was added before transfection of HL-1 cells with S100A8 and S100A9 and measurement of calcium flux. Surprisingly, blocking the RAGE receptor before transfection of S100A8 or S100A9 not only abolished the decrease in calcium flux but actually resulted in increased calcium flux compared with control cells (Figure 7A). Blocking RAGE in the absence of overexpressed S100A8 and S100A9 had no influence on calcium flux (Figure 7A).
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RAGE is known to signal predominantly through NF-B in other cell types. We confirmed that S100A8 and S100A9 could induce NF-B activity in HL-1 cardiomyocytes and that blocking RAGE abolished this signaling (Figure 7B).
Coimmunoprecipitation Reveals a Physical Interaction Between Cardiac S100A8, S100A9, and SERCA2a
We hypothesized that similar to S100A1, S100A8 and S100A9 may interact within the cardiomyocyte with 1 or both the calcium-regulating proteins SERCA2a and RyR2, leading to potentiation of the calcium flux. C57BL/6 mice were injected IP with 40 mg/kg LPS to upregulate S100A8 and S100A9. Six hours after injection, hearts were excised and digested to obtain isolated cardiac myocytes. Coimmunoprecipitation was performed with anti-S100A8, anti-S100A9, or nonspecific IgG. The immunoprecipitate was then probed with anti-SERCA2a and anti-RyR2 antibodies. We found that SERCA2a coimmunoprecipitated with both S100A8 and S100A9, demonstrating a strong interaction between SERCA2a and these proteins (Figure 8). No interaction was found between either S100A8 or S100A9 and RyR2 (data not shown).
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Discussion |
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In this study, we propose a novel mechanistic link between activation of TLRs expressed on the surface of cardiomyocytes and the subsequent decrease in cardiac contractility. The key finding in our study is that on stimulation with the bacterial product LPS, the EF-hand proteins S100A8 and S100A9 are upregulated in cardiomyocytes, leading to a RAGE-dependent decrease in cardiac contractility.
Although it has long been recognized that infection leads to abnormalities in cardiovascular function, the link between pathogen recognition and subsequent cardiac dysfunction remains unclear. We have recently shown that cardiomyocytes express multiple TLRs24; this family of receptors is thought to be responsible for innate immune recognition of pathogens and "self" danger molecules such as heat shock proteins. Following stimulation of these receptors with their cognate ligands, cardiomyocytes exhibit decreased contractility both in isolated preparations and in vivo.24 Because TLRs are not known to interact with the cytoskeleton or contractile machinery, the link between TLR activation and subsequent cardiac contractile dysfunction is unlikely to be direct. Furthermore, because the effect on contractility persists in isolated cardiomyocytes, the pathways downstream of TLRs must lead to either an autocrine effect or interaction with key intracellular contractile proteins or both. With these criteria in mind, we used cDNA microarrays to identify S100A8 and S100A9, which are highly regulated by exposure of cardiomyocytes to TLR ligands. S100A8 and S100A9 are small EF-hand proteins that are capable of exerting both autocrine and intracellular effects.42 Unique among the members of the S100 family, as well as the larger EF-hand superfamily, S100A8 and S100A9 are found not only intracellularly but also in the extracellular space.36–38
In this study, we show, for the first time, that exposure to the TLR4 ligand LPS causes an early, large upregulation of S100A8 and S100A9 expression in cardiomyocytes. This occurs both in whole heart tissue exposed to systemic LPS and in isolated cardiomyocytes exposed in vitro to LPS. Because it is extremely difficult in the intact heart to determine which type of cardiac cell is responsible for the production of any given molecule, the use of both systems affords a high degree of certainty that the origin of S100A8 and S100A9 is from cardiomyocytes. How does ligation of cardiomyocyte-expressed TLR4 result in the production of S100A8 and S100A9? TLRs are type I transmembrane receptors consisting of a variable number of extracellular leucine rich repeats linked to a cytoplasmic Toll/interleukin-1 receptor (TIR) homology domain.51 Downstream signaling has been well characterized in TLRs and, although complex, can be divided into major pathways. Activation of most TLRs by ligand binding results in dimerization, a change in conformation, and recruitment of a variety of downstream signaling molecules.52,53 All TLRs can signal via MyD88, and this pathway is considered to play a dominant role in early inflammatory events. MyD88 is recruited to the TIR domain of activated TLRs. MyD88 recruits IRAK-4, which activates IKK, leading to liberation of NF-B from its inhibitor, IB
, and subsequent translocation of NF-B to the nucleus, where it induces proinflammatory cytokine production.54,55 In addition to the MyD88-dependent pathway, alternative signaling pathways have been identified for TLR4. TLR4 induces interferon-β production independent of MyD88,54 which induces STAT1 phosphorylation and proinflammatory gene expression.
Using MyD88 and NF-B null mice, we determined that LPS-induced production of S100A8 and S100A9 is absolutely dependent on MyD88 and that, although NF-B–null mice exhibited a greatly attenuated response to LPS, there remained a significant elevation of both S100A8 and S100A9. Given that MyD88-dependent signaling not involving NF-B is through the mitogen-activated protein kinase (MAPK) cascade (p38 MAPK, extracellular signal-regulated kinase 1/2, and c-Jun N-terminal kinase),56 it seems probable that LPS-induced S100A8 and S100A9 production is dependent on both NF-B and MAPK. Interestingly, NF-B and MAPK are also activated with overexpression of S100A8 and S100A9 in prostate cancer cells,39 raising the possibility that a positive-feedback loop exists both upstream and downstream of S100A8 and S100A9.
We went on to show at both the cellular and the organ level that S100A8 and S100A9 reduce cardiomyocyte contractility, resulting in a reduced cardiac ejection fraction. We further showed that this reduction in contractility is through a RAGE-dependent mechanism. RAGE is a member of the immunoglobulin superfamily, with the extracellular portion of this cell surface receptor responsible for ligand binding.57 Emerging as a key molecule responsible for diverse pathologies, including both vascular58–61 and nonvascular conditions,37,39,40,62 RAGE is a multiligand receptor known to bind advanced glycation end products (AGEs), amphoterin, amyloid β-peptide, and S100A8/S100A9.61 AGEs have been the most studied ligand for RAGE, with particular interest in how this interaction may mediate macrovascular complications associated with hyperglycemia.61 S100A8 and S100A9 are also known to activate RAGE and, depending on the cell type on which RAGE is expressed, can do so in either heterodimeric or homodimeric form.37–40
Extracellular cation flux, most notably Ca2+ and Zn2+, induces conformational change and allows S100A8 and S100A9 to bind to RAGE, initiating signaling events within the cell. In immune cells, the interaction between S100A8/S100A9 and RAGE induces chemotaxis of neutrophils and secretion of proinflammatory cytokines.41 In cardiomyocytes, ligation of RAGE by AGEs is known to impair cardiac calcium flux60 and has been shown to be a key mediator of both the proinflammatory state and contractile dysfunction associated with ischemia/reperfusion.58 Our cardiomyocyte calcium flux and in vivo cardiac EF data suggest that the individual proteins (homodimeric) are capable of mediating reduced cardiac contractility, although it does appear in vivo that S100A8 combined with S100A9 reduces EF more than either given individually.
Although S100A8 and S100A9 do signal through RAGE under inflammatory conditions, with resultant decreased cardiac contractility, RAGE does not appear to have a constitutive effect on cardiomyocyte calcium flux because blocking RAGE under baseline conditions did not result in a change in calcium flux. However, when S100A8 and S100A9 are expressed with RAGE blocked, this resulted in significantly increased cardiomyocyte calcium flux. This augmented flux may reflect the high degree of homology between S100 proteins,63 because S100A1 is known to exert a positive effect on calcium flux and contractility via interaction with, and potentiation of, the calcium-gating proteins SERCA2a and RyR2.25–35 We went on to show through coimmunoprecipitation that both S100A8 and S100A9 do in fact physically interact with SERC2a, whereas no such interaction was found between them and RyR2.
These intriguing observations lead to the conclusion that S100A8 and S100A9 are not only immunologically active chemokines but are, in fact, important molecules with respect to cardiac function. They are produced by cardiomyocytes in response to inflammatory conditions and proceed to act in at least 2 compartments to influence cardiac contractility. The predominant effect is autocrine: extracellular interaction with cardiomyocyte-expressed RAGE results in decreased contractility. The second compartment is intracellular, where their physiological function is unmasked by blocking the more potent RAGE-mediated effects. Within the cell, cardiomyocyte calcium flux is potentiated by both S100A8 and S100A9, possibly through SERCA2a. This last function is speculative because, although our data suggest physical interaction, further investigations would be necessary to infer causation.
It is increasingly recognized that inflammation is a common underlying feature of many cardiac pathologies. TLRs recognize both invasive pathogens and, perhaps more importantly, endogenous markers of tissue damage, raising the strong possibility that this TLR-S100A8/A9 pathway is relevant to a host of inflammatory cardiac conditions such as ischemia, transplant rejection, and autoimmune disorders.
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Acknowledgments |
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Sources of Funding
This work was supported by Canadian Institutes of Health Research. K.R.W. is a Michael Smith Foundation for Health Research Distinguished Scholar. J.H.B. is an IMPACT/Michael Smith Foundation for Health Research Postdoctoral Fellow and a Providence Health Research Institute Physician Scholar.
Disclosures
None.
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Footnotes |
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Original received November 8, 2007; revision received March 25, 2008; accepted March 31, 2008.
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References |
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