Targeted Deletion of Class A Macrophage Scavenger Receptor Increases the Risk of Cardiac Rupture After Experimental Myocardial Infarction
Background— Class A macrophage scavenger receptor (SR-A) is a macrophage-restricted multifunctional molecule that optimizes the inflammatory response by modulation of the activity of inflammatory cytokines. This study was conducted with SR-A–deficient (SR-A−/−) mice to evaluate the relationship between SR-A and cardiac remodeling after myocardial infarction.
Methods and Results— Experimental myocardial infarction (MI) was produced by ligation of the left coronary artery in SR-A−/− and wild-type (WT) male mice. The number of mice that died within 4 weeks after MI was significantly greater in SR-A−/− mice than in WT mice (P=0.03). Importantly, death caused by cardiac rupture within 1 week after MI was 31% (17 of 54 mice) in SR-A−/− mice and 12% (6 of 51 mice) in WT mice (P=0.01). In situ zymography demonstrated augmented gelatinolytic activity in the infarcted myocardium in SR-A−/− mice compared with WT mice. Real-time reverse transcription–polymerase chain reaction at day 3 after MI showed that the expression of matrix metalloproteinase-9 mRNA increased significantly in the infarcted myocardium in SR-A−/− mice compared with WT mice. Furthermore, SR-A−/− mice showed augmented expression of tumor necrosis factor-α and reduction of interleukin-10 in the infarcted myocardium at day 3 after MI. In vitro experiments also demonstrated increased tumor necrosis factor-α and decreased interleukin-10 expression in activated SR-A−/− macrophages.
Conclusions— The present findings suggest that SR-A deficiency might cause impairment of infarct remodeling that results in cardiac rupture via insufficient production of interleukin-10 and enhanced expression of tumor necrosis factor-α and of matrix metalloproteinase-9. SR-A might contribute to the prevention of cardiac rupture after MI.
Received June 13, 2006; accepted February 2, 2007.
Myocardial infarction (MI) causes complex structural alterations that involve both the infarcted and noninfarcted left ventricular (LV) myocardium.1 The dynamic synthesis and breakdown of extracellular matrix (ECM) proteins play an important role in the post-MI LV remodeling,2 which is a compensatory mechanism against LV dysfunction. However, the excessive degradation of ECM components in the infarcted regions appears to lead to pathological cardiac remodeling, which results in LV rupture.3
LV rupture is a lethal complication that accounts for 5% to 30% of in-hospital mortality in patients with acute MI and is most likely to occur during the first week after the onset of symptoms.4 In addition, it is difficult to predict LV rupture in spite of the management of several risk factors such as transmural MI, a first MI, and hypertension. Recent studies have demonstrated that members of the matrix metalloproteinase (MMP) gene family play a central role in the degradation of ECM after MI.5–7 Therefore, MMPs appear to play a major role in post-MI LV rupture. Furthermore, it has been shown that a key component of LV healing and remodeling after MI is the inflammatory response triggered by a wide variety of chemoattractants and inflammatory cytokines, which can modulate post-MI LV tissue repair.8,9 We and others have reported that macrophage infiltration into the infarcted myocardium accelerated LV remodeling via increased activity of MMPs, which indicates macrophages that infiltrate into the infarcted regions are important contributors to the modulation of LV remodeling after MI.10–12
Clinical Perspective p 1911
Class A macrophage scavenger receptor (SR-A) is the prototypic member of an expanding family of membrane receptors collectively termed scavenger receptors. SR-A is also a macrophage-restricted multifunctional molecule.13–15 SR-A can bind with high affinity to an unusually broad range of polyanionic ligands, which includes modified lipoproteins, lipopolysaccharide of Gram-negative bacteria, lipoteichoic acid of Gram-positive species, β-amyloid, and advanced glycation end products. On the basis of this broad ligand specificity, SR-A may play a role in a wide range of macrophage-associated physiological and pathophysiological processes.16 Previous studies reported that SR-A was associated with the modification of atherosclerosis, macrophage adhesion, host defense, clearance of dying cells, and nervous system disorders. Moreover, Cotena et al recently showed that SR-A could ensure an inflammatory response of the appropriate magnitude via modulation of the activities of proinflammatory receptors and the production of several chemokines.17 This suggests that SR-A might regulate inflammation itself and consequent tissue remodeling via macrophage function in the pathological conditions such as MI. However, there is no evidence that shows the involvement of SR-A in LV remodeling after MI. In the current paper, we report that a deficiency in the SR-A gene (SR-A−/−) contributes to the risk of cardiac rupture after experimental MI via the modification of inflammatory cytokines and MMP expression.
Mice with targeted disruption of the SR-A gene (SR-A−/−),18 which is essential for the formation of SR-A, were used after at least the 8th backcross into the control C57BL/6J strain was reached.19 Genotyping of animals was performed by use of polymerase chain reaction (PCR) of DNA obtained from tail biopsies. Recipient C57BL/6J mice and wild-type (WT) mice of the same genetic background were originally purchased from the Jackson Laboratory (Bar Harbor, Me). SR-A−/− and WT male mice were bred at the Animal Resource Facility at the Kumamoto University under specific pathogen-free conditions. All animal procedures were approved by the Animal Research Committee at Kumamoto University, and all procedures conformed to the Guide for the Care and Use of Laboratory Animals by the Institute of Laboratory Animal Resources. The SR-A−/− and WT mice were fed a regular chow diet and were used for experiments between 8 and 12 weeks of age.
Left Coronary Ligation
Mice were anesthetized with pentobarbital sodium (70 mg/kg) via intraperitoneal injection, and MI was induced by permanent occlusion of the left anterior descending coronary artery with an 8-0 Prolene suture under artificial ventilation, as previously described by our laboratory.10 Significant electrocardiographic and color changes in the ischemic area were considered indicative of successful coronary occlusion. In the sham experiments, the same surgical procedure was performed, with the exception of coronary ligation.
To evaluate survival after MI, the operation and autopsy were performed by a group of investigators who were blinded to the results of the genotyping. SR-A−/− and WT mice underwent coronary artery ligation and were monitored rigorously for morbidity and mortality. Autopsy was immediately performed in each animal after death to determine the cause of death, particularly with reference to cardiac rupture.
Echocardiography and Organ Weight Measurement for Assessment of LV Function
Echocardiographic measurements at baseline and on days 7 and 28 after surgery were performed with a Sonos 4500 with a high-frequency transducer (12 MHz; Philips Co., Tokyo, Japan) as previously described.10,20 Good 2-dimensional views of the LV were obtained for guided M-mode measurements of interventricular septal wall thickness (IVS), posterior wall thickness (PW), LV end-diastolic diameter (LVDd), and end-systolic diameter (LVDs) as surrogate markers of LV dilatation caused by LV remodeling. M-mode percent fractional shortening (%FS) and LV mass were calculated by the following formulas:
respectively.21 After in vivo echocardiographic studies at day 7 post-MI, the heart and lung were excised and their weights were determined. Moreover, the lungs were used to determine water content as a marker of lung congestion by calculation of the wet-to-dry ratio after desiccation for 24 hours at 50°C.22
Light Microscopy and Morphometric Analysis
At days 1, 3, 5 and 7 after coronary ligation, mice were euthanized for gross and microscopic cardiac analysis, with 6 to 10 animals studied at each time point. Heart tissues were fixed in 4% paraformaldehyde solution at 4°C for 4 hours, embedded in OCT compound (Sakura Finetechnical Co., Tokyo, Japan), frozen in liquid nitrogen, and cut by a cryostat into sections 6 μm thick. Sections were routinely stained with hematoxylin and eosin for light microscopy and with Masson’s trichrome for evaluation of myocardial fibrosis. Infarct size and infarct area were determined by a previously reported method.10 In brief, infarct size (%) was calculated as the total infarct circumference divided by the total LV circumference times 100; infarct area was calculated as the percentage of MI area relative to the entire LV tissue area.
Immunohistochemistry was performed according to an indirect immunoperoxidase method with the following antibodies: anti-CD204 for SR-A (2F8; Serotec, Oxford, UK); anti-CD68 for macrophages (FA-11; Serotec); anti-Ly-6G for granulocytes (Gr-1; Southern Biotechnology, Birmingham, Ala); anti-CD31 for endothelial cells (MEC13.3; Pharmingen, San Diego, Calif); anti–smooth muscle α-actin for myofibroblasts (1A4; Dako, Glostrup, Denmark). After inhibition of endogenous peroxidase activity by the method of Isobe et al,23 the sections were incubated with the monoclonal antibodies described above at 4°C overnight. Goat anti-rat Ig-conjugated peroxidase-labeled polymer amino acid (Nichirei, Tokyo, Japan) was used as the secondary antibody. After visualization with 3,3′-diaminobenzidine, sections were stained with hematoxylin for nuclear staining and were mounted with resin. As negative controls, the same procedures were performed but without the primary antibodies. For cell enumeration, the number of positive cells in the infarcted region for each antibody was counted and expressed as the number per mm2.
Detection of Gelatinolytic Activity by In Situ Zymography
To detect gelatinolytic activity in the infarcted heart tissues, we performed in situ zymography by use of a previously reported approach.10 Gelatin films with sections were incubated for 6 hours at 37°C in a moisture chamber and stained with Biebrich Scarlet solution (Wako, Osaka, Japan). The gelatin in contact with the proteolytic areas of the sections was digested, which demonstrated zones of enzymatic activity indicated by negative staining.
Real-Time Reverse Transcriptase-PCR Assay
Total RNA from heart tissues at day 3 after MI was extracted by the RNAzol B method (Tel-Test Inc., Friendswood, Tex). Total RNA was reverse-transcribed into cDNA using random primers (Life Technologies Inc., Rockville, Md). For detection of MMP-2, MMP-9, tissue inhibitor of metalloproteinase-1 (TIMP-1), TIMP-4, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-10 and transforming growth factor-β (TGF-β) mRNA levels in heart tissue, real-time reverse transcriptase PCR was performed with an Applied Biosystems 7300 Real-time PCR System with TaqMan Universal PCR Master Mix and TaqMan Gene Expression Assays (Applied Biosystems, Foster City, Calif). Ribosomal eukaryotic 18S RNA (Applied Biosystems) was used as an endogenous control gene. A standard curve for the serial dilution of murine heart cDNA was generated. The amplification cycle consisted of 2 minutes at 50°C, 10 minutes at 95°C, 15 seconds at 95°C, and 1 minute at 60°C. The mRNA levels were normalized to the endogenous 18S ribosomal RNA gene expression.
In Vitro Assay of Cell Culture of Peritoneal Macrophages
To clarify the role of SR-A in the alteration of cytokine production in macrophages, we employed an in vitro assay system of peritoneal macrophages. Peritoneal macrophages were collected and suspended in RPMI 1640 medium (Sigma, St. Louis, Mo) that was supplemented with 10% fetal calf serum, 0.1 mg/mL streptomycin, and 100 U/mL penicillin, and then sowed at the density of 1.0×106/well on a plastic 24-well plate (Corning, Inc, Corning, NY).24 The multiwell plate was incubated for 2 hours at 37°C in a humidified incubator with 5% CO2. Each well was washed 10 times with 1 mL of PBS to remove nonadherent cells and was assigned either to receive acetylated low-density lipoprotein as a ligand for SR-A or not. Adherent macrophages were additionally cultured for 6 hours or 12 hours, and the supernatant was collected to determine the levels of TNF-α and IL-10 with sandwich ELISA. The assay was performed with commercially available mouse TNF-α ELISA kit (BioSource International, Camarillo, Calif) and mouse IL-10 Quantikine kit (R&D Systems, Minneapolis, Minn). Furthermore, to determine the inhibitory effects of recombinant mouse IL-10 (rmIL-10; R&D Systems) on TNF-α production of activated macrophages, we incubated peritoneal macrophages from both SR-A−/− and WT mice with 50 ng/mL and 200 ng/mL of rmIL-10 simultaneously with acetyl–low-density lipoprotein, a ligand for SR-A.
Data are expressed as mean±2 SEM. Analyses of survival after MI were carried out by the Kaplan-Meier method with the log-rank test to compare survival curves between groups. Group comparisons were made with χ2 tests for nominal data, and unpaired t tests or Mann-Whitney U tests were used for continuous data. Results with P<0.05 were considered statistically significant.
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
Survival and Cardiac Rupture After MI
The post-MI survival rates of SR-A−/− and WT mice were compared. There were no deaths in the sham-operated groups. As shown in Figure 1A, WT mice (84%, 43 of 51 mice) had significantly better survival after MI compared with SR-A−/− mice (67%, 36 of 54 mice). Interestingly, the most frequent cause of death in both SR-A−/− (17 of 18 mice) and WT (6 of 8 mice) mice was LV rupture, which was confirmed by blood coagulation around the pericardial sac and small slits commonly observed in the LV wall. As shown in Figure 1B, the number of the mice that died of LV rupture, which occurred within 5 days, was significantly greater in SR-A−/− mice (31%, 17 of 54 mice) than in WT mice (12%, 6 of 51 mice; P=0.01). During the experiments, no mice in either group were observed to have died from infectious diseases.
Physiological and Echocardiographic Measurement
As shown in Table 1, there were no significant differences in body weight, LVDd, M-mode %FS, LV mass at baseline or at days 7 and 28 post-MI between the 2 groups. Body weight, LVDd, and LV mass increased, and M-mode %FS decreased in both SR-A−/− and WT mice at days 7 and 28 post-MI. However, there were no significant differences between the 2 groups. Interestingly, relative heart weight (heart weight/body weight), relative lung weight (lung weight/body weight) and lung wet-to-dry ratio increased significantly in SR-A−/− mice compared with WT mice at day 7 post-MI.
Histomorphometric and Immunohistochemical Analysis
To evaluate the role of SR-A in the extent of ischemic damage in the infarcted myocardium, infarct size and infarct area were measured at day 7 post-MI. Histological analysis demonstrated that sham-operated myocardium had no signs of myocardial degeneration such as necrosis, fibrosis, hypertrophic change, or inflammatory response. As shown in Table 1, infarct size and area were nearly identical between the 2 groups (54.6±4.9% and 41.8±5.5%, respectively, for SR-A−/− versus 53.5±4.0% and 43.1±3.9%, respectively, for WT). Immunohistochemical analysis revealed the gradual infiltration of FA-11–positive macrophages into the infarcted region, which peaked at day 5 post-MI (Figure 2B). The accumulation of Gr-1–positive granulocytes into the infarcted region increased earlier, peaked at day 3 after MI, and gradually decreased in both groups (Figure 2C). The temporal change in infiltration of these inflammatory cells was identical between the 2 groups. In addition, immunostaining for CD31 and anti–smooth muscle α-actin revealed a similar presence of new blood vessels and myofibroblasts in the infarcted region of both groups (Figure 2A). SR-A–positive cells gradually appeared in the infarcted region of WT mice, although these cells were not observed in the preinfarcted heart tissues from both groups. The spatial and temporal SR-A expression corresponded to that of FA-11–positive macrophages. SR-A−/− mice were not immunopositive for the SR-A antibody at all, in contrast to WT mice (Figure 2A).
Masson’s trichrome staining showed impaired healing of the infarcted myocardial tissue in SR-A−/− mice. That is, as shown in Figure 3A and 3C, there were loosely distributed collagen fibers and the retention of unprocessed necrotic myocardium in the infarcted region in SR-A−/− mice at day 7 post-MI. Conversely, as shown in Figure 3B and 3D, there was dense fibrosis in the entire infarcted region in WT mice.
MMP Expression and Activation in Infarcted Region
To evaluate the expression of MMPs and TIMPs, which play an important role in cardiac rupture after MI, we quantified cardiac MMP-2, MMP-9, TIMP-1, and TIMP-4 mRNA levels in SR-A−/− and WT mice. As shown in Figure 4A, the expression of MMP-9 mRNA increased significantly in the infarcted region compared with the noninfarcted or sham-operated myocardial tissues at day 3 post-MI in both SR-A−/− and WT mice, and was greater in the infarcted region of SR-A−/− mice than in that of WT mice. TIMP-1 mRNA expression also increased significantly in the infarcted region compared with the noninfarcted or sham-operated myocardial tissues at day 3 post-MI in both groups, and was inhibited more strongly in the infarcted region of SR-A−/− mice than WT mice. On the other hand, there was no significant difference in MMP-2 and TIMP-4 mRNA expression in the infarcted region between the SR-A−/− and WT mice, although MMP-2 mRNA was upregulated, and TIMP-4 mRNA was downregulated in the infarcted region compared with the noninfarcted or sham-operated myocardial tissues at day 3 post-MI in both SR-A−/− and WT mice.
We performed in situ zymography with gelatin films to detect gelatinolytic activity derived from the augmented MMP-9 mRNA expression in infarcted myocardial tissue. No gelatinolytic activity was detected at 1 day post-MI in either group (data not shown). In situ zymography demonstrated greater gelatinolytic activity in the infarcted region of SR-A−/− mice than WT mice at day 5 post-MI (Figure 4B). Moreover, morphometrically quantitative analysis of the gelatinolytic area/infarct area at day 5 post-MI confirmed the increased gelatinolytic activity in SR-A−/− mice (Figure 4C).
Expression of Inflammatory Cytokines
To examine the molecular mechanism that underlies the increased MMP activity in SR-A−/− mice, we determined cardiac mRNA expression of several cytokines and growth factors by real-time reverse transcriptase PCR. Interestingly, the proinflammatory cytokine TNF-α mRNA was upregulated in the infarcted region compared with the noninfarcted or sham-operated myocardial tissues at day 3 post-MI in both SR-A−/− and WT mice, and was greater in the infarcted region of SR-A−/− mice than WT mice (Figure 5A). The quantification of protein levels by ELISA also demonstrated upregulated TNF-α protein expression in the infarcted region of SR-A−/− mice (Figure 5E). In contrast, the antiinflammatory cytokine IL-10 mRNA was also upregulated in the infarcted region compared with the noninfarcted or sham-operated myocardial tissues at day 3 post-MI in both SR-A−/− and WT mice, and was significantly lower in the infarcted and noninfarcted region of SR-A−/− mice than WT mice (Figure 5B). Although other mRNAs of inflammatory cytokines and growth factors such as TGF-β, which appeared to regulate the synthesis and breakdown of ECM components, were also induced in the infarcted region compared with the noninfarcted region or sham-operated tissues, there were no significant differences between SR-A−/− and WT mice (Figure 5C and 5D).
In Vitro Analysis With Peritoneal Macrophages
We conducted in vitro experiments with peritoneal macrophages to confirm whether the imbalance in production of inflammatory cytokines detected in in vivo experiments could be reproduced in vitro. As shown in Figure 6A, IL-10 production increased significantly in both groups after 6 hours of incubation, but not after 12 hours. The levels of IL-10 production were significantly lower in SR-A−/− macrophages than WT macrophages when cultured with SR-A ligand for 6 hours, but not for 12 hours. As shown in Figure 6B, TNF-α production was significantly greater after 12 hours of incubation compared with production after 6 hours in both groups. The levels of TNF-α production were greater in SR-A−/− macrophages than WT macrophages when cultured with SR-A ligand for 12 hours, but not for 6 hours. With respect to the effects of rmIL-10 addition, the levels of TNF-α production by activated macrophages were significantly downregulated in both SR-A−/− and WT macrophages after administration of 50 ng/mL rmIL-10, and the difference between both macrophages was diminished (Figure 6B). In contrast, in the group that received 200 ng/mL rmIL-10, the inhibitory effects on TNF-α production were absent (data not shown).
Our study provided the first evidence that SR-A was essential for normal healing of infarcted myocardium. Specifically, we showed that SR-A−/− mice had a higher mortality mainly as a result of LV rupture after MI. The fragility of the LV wall in SR-A−/− mice might be attributable to markedly enhanced MMP activity in the infarcted myocardium. In the upstream mechanism, SR-A might be involved in the regulation of cytokine production and the ischemia-derived inflammatory response.
In the present study, we found that SR-A−/− mice had loosely distributed collagen fibers and retention of unprocessed necrotic myocardium in the infarcted region stained with Masson’s trichrome. It has been demonstrated that MMPs might be the major pathophysiological regulators of ECM degradation and might be implicated in the pathogenesis of LV remodeling after MI.5 Indeed, several studies in genetically-manipulated mice documented that gelatinases (ie, MMP-2 and MMP-9) play a crucial role in the LV remodeling process and may contribute to LV rupture.6,7,25 Heymans et al demonstrated that MMP-9 deficiency prevented cardiac rupture after MI.7 The significance of MMP-9 activity in early infarct healing and rupture was emphasized by the observation that MMP-9 was predominantly found in leukocytes and macrophages, and that its activity peaked around day 2, the period in which most ruptures occur. In the present study, quantitative reverse transcriptase PCR revealed increased MMP-9 mRNA expression and decreased TIMP-1 mRNA expression in the infarcted region of SR-A−/− mice at day 3 post-MI. In addition, in situ zymography indicated excessive gelatinolytic activity around the infarcted region of SR-A−/− mice. Taking these findings into consideration, enhanced gelatinolytic activity may directly contribute to the increased risk of post-MI LV rupture in SR-A−/− mice.
With regard to the upstream mechanism under the augmented MMP activity, Jugdutt reported that the net proteolytic activity of MMPs depended on transcription, activation, and inhibition of these molecules.26 Transcription from MMP genes to pro-MMPs is stimulated by several factors such as inflammatory cytokines and growth factors.27 Indeed, Sun et al recently showed that elevated local TNF-α in infarcted myocardium of TNF-α–deficient mice contributes to acute cardiac rupture via augmented MMP-9 expression.28 TNF-α is a master proinflammatory cytokine that is produced in the infarcted myocardium very soon after MI and is potentially a major contributor to post-MI LV rupture.28,29 On the other hand, antiinflammatory cytokines such as IL-10 are thought to have a protective role after MI through the suppression of the acute inflammatory process.30–32 Very recently, Fulton et al demonstrated that SR-A−/− mice displayed reduced levels of lipopolysaccharide-induced IL-10 production, which regulated the inflammatory process in endotoxemia and sepsis.33 Consistent with these findings, our data revealed that the expression of IL-10 mRNA was attenuated in the infarcted region of SR-A−/− mice compared with WT mice at day 3 post-MI. On the other hand, the expression of TNF-α mRNA increased significantly more in the infarcted region of SR-A−/− mice than in that of WT mice at day 3 post-MI. Moreover, we subsequently performed in vitro experiments with peritoneal macrophages to verify the contribution of SR-A to the imbalanced production of these proinflammatory and antiinflammatory cytokines. The present findings suggested that SR-A deficiency might enhance TNF-α secretion as a result of the suppression of IL-10 secretion in SR-A−/− macrophages. The imbalance of the production of inflammatory cytokines could be responsible for the markedly augmented MMP activity and increased risk of post-MI LV rupture. Furthermore, we showed the inhibitory effects of rmIL-10 administration on TNF-α secretion in the cell culture experiments. The more intense effect was observed in SR-A−/− macrophages. Therefore, SR-A–mediated IL-10 production may be a key step involved in the regulation of TNF-α production in activated macrophages.
In addition, organ weight analysis indicated that heart weight, lung weight, and lung wet-to-dry ratio increased significantly in SR-A−/− mice compared with WT mice at day 7 post-MI. These results suggested the exacerbation of post-MI myocardial hypertrophy or lung injury in SR-A−/− mice. The putative mechanisms for these findings include a direct effect of upregulated TNF-α on myocardial hypertrophy or lung congestion based on the adverse influence of TNF-α on post-MI heart and lung tissues.28,34,35 In the present study, however, there was no significant difference in the echocardiographic measurements of LV cavity dimensions, M-mode %FS, and LV mass between the 2 groups. We must emphasize that echocardiographic measurements and histomorphological and biological analyses could only be performed in the surviving mice. It is possible that the degree of LV expansion, LV wall thinning, and LV dysfunction might have been greater in the mice that died as a result of early cardiac rupture and this may have biased the results. In addition, LV dimensions and function could have been greatly influenced by the stage of the anesthesia and hemodynamic parameters such as heart rate.20 The reason why there were no significant differences in echocardiographic measurements between the 2 groups might have been caused by the exclusion of nonsurviving mice or hemodynamic changes as a result of anesthesia.
In summary, the present findings provide the first evidence of a pathophysiological role for SR-A in LV remodeling after MI and add further support for the importance of macrophages in the healing process after MI. Further research about the SR-A–related signaling pathway might provide innovative therapeutic approaches to prevent cardiac rupture after MI.
We thank Emi Kiyota, Takenobu Nakagawa, Osamu Nakamura, and Junichi Yoshida, from the Department of Cell Pathology, Kumamoto University, for their skillful technical assistance.
Sources of Funding
The present study was supported in part by a Grant from the Japan Heart Foundation and a Grant-in-Aid for Scientific Research (B-16390108, B-17390115, B-17390232, and C-17590752) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.
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Despite improved treatments for acute myocardial infarction (MI), post-MI cardiac rupture remains a serious acute complication. Unfortunately, cardiac rupture mainly develops in younger patients with a transmural MI and is also unpredictable and fatal because of the absence of treatment. Accumulated experimental and clinical studies have indicated that members of the matrix metalloproteinase gene family play a central role in pathogenesis of cardiac rupture. Furthermore, we believe that understanding inflammatory response is critical for the prevention of post-MI cardiac rupture because the matrix metalloproteinase activation may be regulated mainly by various inflammatory mediators. In the present study, we evaluated the role of class A macrophage scavenger receptor (SR-A), which was a macrophage-restricted multifunctional molecule that optimized the inflammatory response in post-MI tissue repair. Our data revealed that a deficiency in the SR-A gene increased the risk of cardiac rupture after experimental MI via enhanced matrix metalloproteinase expression in infarcted myocardium. Moreover, we observed that SR-A deficiency enhanced tumor necrosis factor-α secretion as a result of the suppression of interleukin-10 secretion in SR-A–deficient macrophages. These findings suggest that SR-A might regulate macrophage-associated inflammatory responses in infarcted regions and might modulate consequent tissue remodeling in the healing process after MI. Further research into the SR-A–related signaling pathway might provide innovative therapeutic approaches to prevent cardiac rupture.