Author + information
- Received September 19, 2011
- Revision received October 19, 2011
- Accepted October 20, 2011
- Published online February 28, 2012.
- Toyoharu Oba, MD⁎,
- Hideo Yasukawa, MD, PhD⁎,†,⁎ (, )
- Masahiko Hoshijima, MD, PhD‡,
- Ken-ichiro Sasaki, MD, PhD⁎,†,
- Nobuyoshi Futamata, MD⁎,
- Daisuke Fukui, MD⁎,
- Kazutoshi Mawatari, MD⁎,
- Takanobu Nagata, MD⁎,
- Sachiko Kyogoku, MD⁎,
- Hideki Ohshima, MD⁎,
- Tomoko Minami, MD⁎,
- Keiichiro Nakamura, MD, PhD§,
- Dongchon Kang, MD, PhD∥,
- Toshitaka Yajima, MD, PhD‡,
- Kirk U. Knowlton, MD‡ and
- Tsutomu Imaizumi, MD, PhD⁎,†
- ↵⁎Reprint requests and correspondence:
Dr. Hideo Yasukawa, Division of Cardiovascular Medicine, Department of Internal Medicine, Cardiovascular Research Institute, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan
Objectives The study investigated the role of myocardial suppressor of cytokine signaling-3 (SOCS3), an intrinsic negative feedback regulator of the janus kinase and signal transducer and activator of transcription (JAK-STAT) signaling pathway, in the development of left ventricular (LV) remodeling after acute myocardial infarction (AMI).
Background LV remodeling after AMI results in poor cardiac performance leading to heart failure. Although it has been shown that JAK-STAT–activating cytokines prevent LV remodeling after AMI in animals, little is known about the role of SOCS3 in this process.
Methods Cardiac-specific SOCS3 knockout mice (SOCS3-CKO) were generated and subjected to AMI induced by permanent ligation of the left anterior descending coronary artery.
Results Although the initial infarct size after coronary occlusion measured by triphenyltetrazolium chloride staining was comparable between SOCS3-CKO and control mice, the infarct size 14 days after AMI was remarkably inhibited in SOCS3-CKO, indicating that progression of LV remodeling after AMI was prevented in SOCS3-CKO hearts. Prompt and marked up-regulations of multiple JAK-STAT–activating cytokines including leukemia inhibitory factor and granulocyte colony-stimulating factor (G-CSF) were observed within the heart following AMI. Cardiac-specific SOCS3 deletion enhanced multiple cardioprotective signaling pathways including STAT3, AKT, and extracellular signal-regulated kinase (ERK)-1/2, while inhibiting myocardial apoptosis and fibrosis as well as augmenting antioxidant expression.
Conclusions Enhanced activation of cardioprotective signaling pathways by inhibiting myocardial SOCS3 expression prevented LV remodeling after AMI. Our data suggest that myocardial SOCS3 may be a key molecule in the development of LV remodeling after AMI.
Left ventricular (LV) remodeling after acute myocardial infarction (AMI) is characterized by infarct expansion, LV dilation, and fibrosis of viable myocardium (1–3). This adverse LV remodeling depresses cardiac performance, contributes to the development of heart failure, and is an independent determinant of morbidity and mortality after AMI (1–3). Although several major therapeutic advances have been made in the management of AMI, the number of patients with congestive heart failure is increasing; these patients carry a >10-fold increased risk of death (1–3). Accordingly, it is important to elucidate the mechanisms underlying post-infarct LV remodeling and to develop therapeutic strategies that will effectively suppress this adverse process (1,4).
The administration of cytokines such as granulocyte colony-stimulating factor (G-CSF), erythropoietin, interleukin (IL)-11, and leukemia inhibitory factor (LIF) was recently demonstrated to prevent the development of LV remodeling after AMI in animals (5–11). These cytokines activate the janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathways, which have protective roles in the development of LV remodeling after AMI (12–16). Although JAK-STAT–activating cytokines prevent LV remodeling after AMI in animals, little is known about the role of a negative feedback regulator for the JAK-STAT signaling pathway in this process.
Suppressor of cytokine signaling (SOCS) family proteins were identified as cytokine-inducible intrinsic inhibitors of cytokine signaling (17,18). We demonstrated previously that SOCS1 and SOCS3 strongly inhibit JAK-STAT–mediated cytokine signaling pathways as pseudosubstrates by interacting with JAK and inhibiting JAK activity (17–19). SOCS3 is induced by JAK-STAT–activating cytokines, including G-CSF, erythropoietin, and LIF, and acts to inhibit their actions (18–20). We previously showed that the forced expression of SOCS3 inhibited cytokine-promoted cardiomyocyte survival in vitro and that cardiac-specific transgenic expression of SOCS3 facilitated coxsackievirus-induced cardiac injury in mice by inhibiting the JAK-STAT signaling pathway (20–22). Thus, SOCS3 is a cytokine-inducible inhibitor of the JAK-STAT pathway that promotes myocardial cell survival. Therefore, we hypothesized that the inhibition of myocardial SOCS3 would prevent LV remodeling after AMI. To test this hypothesis, we generated cardiac-specific SOCS3 knockout mice (SOCS3-CKO) using the Cre recombinase and loxP system (23). We then induced AMI in these mice by permanently ligating the left anterior descending coronary artery, and investigated the role of myocardial SOCS3 in the development of LV remodeling after AMI.
Generation of SOCS3-CKO
Because SOCS3-deficient mice die during embryonic development as a result of placental defects, the SOCS3 coding region in exon2 was flanked by loxP sites (flox) (Fig. 1A), and we generated SOCS3-flox mice to determine the tissue-specific roles of SOCS3 (23,24). To investigate the role of JAK-STAT signaling and its negative regulator SOCS3 in LV remodeling after AMI, SOCS3-flox mice were bred with α-myosin heavy chain–promoter-driven cardiac-specific Cre recombinase transgenic mice (25). We confirmed that SOCS3 protein was markedly reduced in SOCS3-CKO hearts 6 h after intraperitoneal injection of lipopolysaccharide (LPS) (20 mg/kg) (Fig. 1B).
The mice used in this study were 8- to 10-week-old males in a Balb/c background. All experimental procedures were performed according to the guidelines for experiments in animals established by the Kurume University Animal Care and Treatment Committee for experiments in animals.
Acute myocardial infarction model
Acute myocardial infarction was produced by permanent ligation of the left coronary artery as previously described. To measure infarct size 14 days after AMI, the LV were cut into 3 transverse sections from apex to base. Five-micrometer sections were stained with Mallory-AZAN staining. The extent of fibrosis was measured in 3 sections and the value was expressed as the ratio of Mallory-AZAN–stained area to total LV free wall (5). Evans blue dye and triphenyltetrazolium chloride (TTC) stains were also performed to measure initial infarct size. Area at risk and infarct area were determined by perfusion with 5% Evans blue and consequent incubation with TTC at 3 h after left coronary artery occlusion, as previously described (12).
Western blot analysis
Western blot analysis was performed as described previously (20–22) with the use of antibodies raised against tyrosine-phosphorylated STAT3, serine-phosphorylated STAT3, phosphorylated AKT, phosphorylated extracellular signal-regulated kinase (ERK)-1/2, Bcl-xL, Bad, Bax, and cleaved caspase 3 antibodies (New England BioLabs, Beverly, Massachusetts); SOCS3 (Immuno-Biological Laboratories, Takasaki, Japan); cytochrome c (BD Pharmingen, Franklin Lakes, New Jersey); porin (Invitrogen, Carlsbad, California); tubulin (Santa Cruz Biotechnology, Santa Cruz, California); mitochondrial transcriptional factor A (TFAM) (26); manganese superoxide dismutase (Mn-SOD); and heme oxygenase (HO)-1 (Abcam, Cambridge, United Kingdom).
To detect apoptosis, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining was performed according to the manufacturer's protocol (In Situ Apoptosis Detection kit; Takara Bio Inc., Otsu, Japan). Digital photographs were taken at 400× magnification, and 25 random high-power fields from each heart sample were chosen and quantified.
RNA extraction and real-time PCR
Total LV ribonucleic acid (RNA) was isolated using TRIzol (Invitrogen) as described previously (20–22), and 1 μg of total RNA was converted into complimentary deoxyribonucleic acid. Expression profiles of common cytokines were performed with the RT2 Profiler polymerase chain reaction (PCR) array for murine common cytokines (SABiosciences, Frederick, Maryland), according to the manufacturer's instructions. Polymerase chain reaction was performed with the StepOne real-time PCR machine (Applied Biosystems, Foster City, California). The ΔΔCt method was used to analyze the expression level of each gene. After PCR, the dissociation curve for each gene was examined to exclude genes with nonspecific amplification or undetectable expression. The expression profile of each gene was displayed as a heat map made by using MeV MultiExperiment Viewer 4.1 (Institute for Genomic Research, Rockville, Maryland). Real-time PCR assays were also performed to assess the gene expression of mouse SOCS1, SOCS2, SOCS3, cytokine-inducible SH2 protein (CIS), peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α), collagen 1, and collagen 32, and GADPH with the corresponding primer pairs (Applied Biosystems, #Mm00782550_s1 refer to SOCS1, #Mm00850544 g1 refer to SOCS2, #Mm00545913 s1 refer to SOCS3, #Mm01230623_g1 refer to CIS, #Mm01208835_m1 refer to PGC-1α, Mm01254476_ml refer to collagen 3, and #Mm99999915_g1 refer to GADPH, respectively) using the StepOnePlus Real-Time PCR System (Applied Biosystems).
At 14 days after AMI, transthoracic echocardiographic studies were performed under light anesthesia using a Vevo770 ultrasound machine (VisualSonics Inc., Toronto, Ontario, Canada) equipped with a 30-MHz probe. Mice were anesthetized with isoflurane and subjected to echocardiography as previously described (20–22). Recording was performed as described previously (20–22).
Data are expressed as mean ± standard error (SE). Multiple group comparisons were performed using 1-way analysis of variance followed by the Bonferroni procedure for comparison of means (Figs. 2C, 3B, 4B, 6A, 7A, and 9A). Comparison of 2 groups was analyzed using 2-tailed Student's t test. Survival analysis was performed using the Kaplan-Meier method, and between-group differences in survival were tested using the log-rank (Mantel-Cox) test; p values <0.05 were considered statistically significant.
Basal phenotype of SOCS3-CKO
SOCS3-CKO pups were born in an expected Mendelian ratio and grew to adulthood normally. We confirmed by Western blot that SOCS3 expression was induced in LPS-injected hearts of control mice. SOCS3 expression was markedly reduced in LPS-injected SOCS3-CKO hearts, and was accompanied by enhanced STAT3 phosphorylation (Fig. 1B). We also confirmed using real-time PCR that SOCS3 messenger RNA was markedly reduced in SOCS3-CKO hearts 2 days after AMI, and that the expression of other SOCS family genes including SOCS1 were not altered in controls or SOCS3-CKO hearts (Fig. 1C). Histological examination of SOCS3-CKO hearts at 16 weeks revealed no evidence of necrosis or ventricular fibrosis. Echocardiography confirmed preserved LV function and wall thickness in SOCS3-CKO, comparable to littermate controls (data not shown).
Prevention of post-infarct LV remodeling and mortality in SOCS3-CKO
We first evaluated the initial infarct size 3 h after coronary ligation using Evans blue dye and TTC staining. Both the area at risk and infarct size immediately after AMI were comparable between controls and SOCS3-CKO (Fig. 2A). We then compared the survival rate between controls and SOCS3-CKO. Approximately 45% of controls died within 14 days after AMI (Fig. 2B). In contrast, all SOCS3-CKO survived up to 14 days after AMI. The increases in LV weight-to-body-weight ratio and lung weight-to-body-weight ratio 14 days after AMI were significantly attenuated in SOCS3-CKO compared with controls (Fig. 2C). Mallory-AZAN staining revealed that the infarct area of hearts 14 days after AMI was significantly smaller in SOCS3-CKO than in controls (Fig. 2D). Echocardiographic assessment consistently revealed that anterior wall thickness was greater, LV end-diastolic dimension was smaller, and ejection fraction was greater in SOCS3-CKO than in controls 14 days after AMI (Fig. 3). Thus, post-infarct LV remodeling and mortality were significantly prevented in SOCS3-CKO.
Enhanced activation of cardioprotective signaling pathways in SOCS3-CKO after AMI
Next, we compared the activation of cardioprotective signaling pathways including STAT3, STAT1, AKT, and ERK1/2 after AMI in controls and SOCS3-CKO using Western blot analysis. Whereas STAT3 and STAT1 were promptly phosphorylated and AKT was phosphorylated 3 days after AMI, ERK1/2 phosphorylation was down-regulated up to 7 days after AMI in controls (Fig. 4A). Consistent with a previous report that cytokine-induced SOCS3 expression is STAT3-dependent, SOCS3 induction was closely correlated with STAT3 activation in the hearts of controls. In SOCS3-CKO hearts compared with controls, STAT3 phosphorylation was greater and more sustained, STAT1 phosphorylation was less, and phosphorylation of AKT and ERK1/2 was more rapid and greater up to 14 days after AMI (Fig. 4A). Thus, the activation of cardioprotective signaling pathways including STAT3, AKT, and ERK1/2 after AMI was enhanced in SOCS3-CKO compared with controls. We also conducted immunohistochemical staining of phosphorylated STAT3 in the heart after AMI. The number of phosphorylated STAT3 positive cells was significantly greater in SOCS3-CKO hearts than that in control hearts in both the border area and the remote area (Fig. 4B).
Cytokine-rich microenvironment in the heart after AMI
To determine which cytokine activates JAK downstream signaling pathways in the heart after AMI, we conducted real-time PCR analysis for cytokines on mice hearts 2 days after AMI. Multiple cytokines that activate the JAK-STAT pathway and induce SOCS3 expression were highly expressed in the heart after AMI, demonstrating the presence of a cytokine-rich microenvironment in the ischemic myocardium (Fig. 5). Expressions of several cytokines including G-CSF and IL-11 were lower in SOCS3-CKO hearts than that in controls (Fig. 5).
Inhibition of cardiomyocyte apoptosis in SOCS3-CKO after AMI
To determine the mechanism underlying how SOCS3 deletion in cardiomyocytes prevents the development of LV remodeling, we first measured the number of apoptotic cells by TUNEL staining 24 h after AMI. The number of TUNEL-positive cells was significantly smaller in SOCS3-CKO hearts than in controls (Fig. 6A). Western blot analysis revealed that expression of the antiapoptotic molecule Bcl-xL was much greater in SOCS3-CKO than in controls. On the other hand, the expression of proapoptotic molecules Bad and Bax was less in SOCS3-CKO than in controls (Fig. 6B). The release of cytochrome c into the cytosol after AMI was also smaller in SOCS3-CKO hearts than in controls (Fig. 7A).
Increased PGC-1α and TFAM expressions in SOCS3-CKO hearts after AMI
Because PGC-1α and TFAM play important roles in cardiac mitochondrial biology (26–28), we examined PGC-1α and TFAM expressions in infarct hearts using real-time PCR and Western blot analysis, respectively. We observed that PGC-1α expression after AMI was greater in SOCS3-CKO hearts than in controls (Fig. 7B). We observed that TFAM expression was much greater in SOCS3-CKO hearts than in controls (Fig. 7C). Additionally, we conducted immunohistochemical staining of TFAM in the heart after AMI. The number of TFAM-positive cells was significantly greater in SOCS3-CKO hearts than in controls, both in the border area and in the remote area (Fig. 7D).
Enhancement of antioxidant enzymes expression in SOCS3-CKO hearts after AMI
It is well known that mitochondria are major sources of reactive oxygen species (ROS) and that ROS themselves promote mitochondria-mediated myocardial apoptosis (28,29). Antioxidants such as Mn-SOD and HO-1 prevent LV remodeling after AMI (30,31). Western blot analysis revealed that expressions of HO-1 and Mn-SOD were significantly greater in SOCS3-CKO hearts after AMI (Fig. 8).
Decreased cardiac fibrosis in SOCS3-CKO hearts after AMI
Cardiac fibrosis is a critical feature of post-infarct LV remodeling. Therefore, we measured the fibrotic area in Mallory-AZAN–stained hearts 14 days after AMI, and conducted real-time PCR for genes that were involved in fibrosis and related to the JAK-STAT pathway. The fibrotic areas were smaller in SOCS3-CKO hearts than in controls in both infarct and remote areas (Fig. 9A). Expression of matrix metalloproteinase-9, connective tissue growth factor, transforming growth factor β2, collagen 1, and collagen 3 was significantly lower and expression of tissue inhibitor of matrix metalloproteinase-2 was significantly greater in SOCS3-CKO than in controls (Fig. 9B).
In the present study, we attempted to determine the role of SOCS3, which is an intrinsic negative regulator of multiple cytokines, within cardiomyocytes in the development of LV remodeling after AMI. We observed that the deletion of SOCS3 in cardiomyocytes enhanced multiple survival pathways including STAT3, AKT, and ERK1/2; prevented myocardial apoptosis and fibrosis; enhanced the expression of antioxidants; and resulted in the prevention of LV remodeling after AMI. Our findings suggest that cardiac SOCS3 may be a key molecule for the development of LV remodeling after AMI.
We consider that the enhanced survival of SOCS3-CKO after AMI is due to the inhibitions of LV remodeling and the subsequent heart failure. It is possible that the inhibitions of LV remodeling and heart failure after AMI in SOCS3-CKO are due to the decreased infarct size. However, the initial infarct size 3 h after coronary occlusion was similar between SOCS3-CKO and controls. On the other hand, the infarct size 14 days after AMI was significantly smaller in SOCS3-CKO than in controls, indicating that progression of LV remodeling after AMI was inhibited in SOCS3-CKO hearts. On the basis of these results, we will discuss the cardioprotective mechanisms against LV remodeling after AMI in mice with a cardiac-specific SOCS3 deletion.
In our previous study, forced expression of SOCS3 in ventricular cardiomyocytes completely suppressed the antiapoptotic action of cardiotrophin-1 and LIF by inhibiting STAT3, AKT, and ERK1/2 signaling pathways (20), suggesting that cardiac SOCS3 may promote apoptosis under pathological conditions in which JAK-STAT signaling pathways are activated. Consistent with the previous study, Harada et al. (5) recently demonstrated that the cardiac-specific inhibition of STAT3 by the transgenic expression of dominant-negative STAT3 abolished the beneficial effects of G-CSF on LV remodeling after AMI. They proposed that the direct action of G-CSF on cardiomyocytes via the JAK-STAT3 signaling pathway plays a crucial role in preventing myocardial apoptosis after AMI (5). In the present study, SOCS3 was not induced within a few hours after coronary occlusion but was induced several hours after coronary occlusion in control mice. We demonstrated that the cardiac-specific deletion of SOCS3 prevented myocardial apoptosis and LV remodeling after AMI by augmenting STAT3 activation. Although the initial infarct size was comparable between SOCS3-CKO and controls, the number of apoptotic cells 24 h after coronary occlusion was significantly less in SOCS3-CKO than in controls, suggesting that myocardial apoptosis during infarct expansion after AMI was prevented in SOCS3-CKO hearts. Taken together, our results suggest that ischemia-induced SOCS3 induction in cardiomyocytes may facilitate myocardial apoptosis in infarct expansion during LV remodeling after AMI.
Next we investigated the mechanisms underpinning attenuated apoptosis in SOCS3-CKO hearts. We focused on mitochondria of cardiomyocytes for 2 reasons. First, it has been shown that mitochondria play an important role in the regulation of apoptosis. Second, it is well known that the antiapoptotic protein Bcl-xL is a STAT3 target gene, which governs mitochondrial outer membrane permeabilization and suppresses apoptosis (32,33). Recently, Wegrzyn et al. (34) demonstrated a novel function of serine-phosphorylated STAT3 in mitochondrial homeostasis. They reported that serine-phosphorylated STAT3 was present in the mitochondria of primary tissues including the heart, and that the activities of complexes I and II of the electron transport chain were significantly decreased in STAT3-deficient cells (34). In the present study, we have several lines of evidence for preserved mitochondrial function in SOCS3-CKO hearts. We have shown that the release of cytochrome c from mitochondria to the cytosol was prevented in the heart of SOCS3-CKO after AMI (Fig. 7). Both tyrosine-phosphorylated STAT3 and serine-phosphorylated STAT3 were significantly enhanced in SOCS3-CKO hearts (Fig. 4A). We also observed that TFAM (an essential molecule for the mitochondrial deoxyribonucleic acid transcription and replication) (26,35) and PGC-1α (an important regulator of mitochondrial biology in the heart) (27) were transiently up-regulated after AMI, and their expression was enhanced in SOCS3-CKO hearts. Taken together, the present study may indicate that cardiac-specific deletion of SOCS3 enhances STAT3 activation and prevents mitochondria-mediated myocardial apoptosis.
Next we investigated the mechanism underpinning the prevention of mitochondria-mediated myocardial apoptosis in SOCS3-CKO hearts. In addition to the role of mitochondria as a source of ROS, mitochondria themselves are damaged by ROS (28,29). ROS induce myocardial apoptosis, which plays an important role in the development and progression of maladaptive LV remodeling after AMI (28,29). Antioxidant enzymes such as Mn-SOD and HO-1 are defense mechanisms against ROS-mediated myocardial injury. It has been shown that both Mn-SOD and HO-1 prevent myocardial apoptosis and LV remodeling after AMI (30,31). Mn-SOD and HO-1 are target genes of STAT3 (36,37). In the present study, we found that HO-1 expression was transiently and Mn-SOD was gradually up-regulated after AMI in hearts from controls (Fig. 8). Additionally, Mn-SOD and HO-1 expression are enhanced during LV remodeling after AMI in SOCS3-CKO hearts. Therefore, increased Mn-SOD and HO-1 expression may have contributed to the prevention of mitochondria-mediated myocardial apoptosis, leading to the inhibition of LV remodeling after AMI in SOCS3-CKO (Fig. 10).
Cardiac fibrosis is a critical feature of post-infarct LV remodeling. STAT3-activating cytokines such as IL-11, G-CSF, and erythropoietin suppress cardiac fibrosis during AMI (10,38,39). Cardiac-specific STAT3-deficient mice exhibited a marked increase of cardiac fibrosis (40). In this study, we found that cardiac fibrosis in SOCS3-CKO was reduced compared with controls, and that the expressions of connective tissue growth factor, matrix metalloproteinase-9, and transforming growth factor β2, which promote cardiac fibrosis, was reduced in SOCS3-CKO hearts compared with controls. These results suggest that preventions of myocardial apoptosis as well as fibrosis may contribute to the inhibition of post-infarct LV remodeling in SOCS3-CKO.
In this study, the enhancement of STAT3 activation and TFAM expression, and the reduction of fibrotic response, were observed in both infarct and remote viable areas during LV remodeling after AMI. These results suggest an important underlying mechanism by which the myocardium of SOCS3-CKO was protected from either ischemic injury directly or post-AMI stress throughout the myocardium.
Because we demonstrated that myocardial-specific SOCS3 deletion enhanced multiple cardioprotective signaling pathways and ameliorated LV remodeling after AMI, small-molecule antagonist of SOCS3 or tissue-specific vector delivery of SOCS3 inhibitor during LV remodeling after AMI may prove to be a clinically valuable strategy to enhance the protective effect of JAK-STAT–activating cytokines. Recently, the first phase II trial showed that an intravenous bolus of erythropoietin did not reduce infarct size in patients with AMI (41). We previously showed that cytokine-induced SOCS3 confers resistance to cytokine action by inhibiting the JAK-STAT pathway (42,43). Therefore, the strategy of myocardial SOCS3 inhibition may be effective for AMI patients who are resistant to cytokines such as erythropoietin.
We propose that myocardial SOCS3 is a key determinant of LV remodeling after AMI, and SOCS3 may serve as a novel therapeutic target to prevent LV remodeling after AMI. Cardiac-specific STAT3-deficient mice exhibited a maladaptive cardiac remodeling with aging (40). Therefore, although the experiments reported here were restricted to young mice, the long-term effects of SOCS3 deletion remain to be determined.
The authors thank Dr. Kenneth Chien for generating SOCS3-flox mice. They also thank Kimiko Kimura, Miyuki Nishigata, Makiko Kiyohiro, and Miho Kogure for excellent technical assistance.
This study was supported by Grants-in-Aid for Scientific Research, the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NIBIO); a grant for the Academic Frontier Project from the Ministry of Education, Science, Sports, Culture, and Technology, Japan; Mochida Memorial Foundation; Uehara Memorial Foundation; and Takeda Memorial Foundation. All authors have reported that they have no relationships relevant to the contents of this paper to disclose. Douglas Mann, MD, served as Guest Editor for this article.
- Abbreviations and Acronyms
- acute myocardial infarction
- cardiac-specific knockout mice
- extracellular signal-regulated kinase
- flanked byloxP site
- granulocyte colony-stimulating factor
- heme oxygenase
- janus kinase
- leukemia inhibitory factor
- left ventricular
- manganese superoxide dismutase
- polymerase chain reaction
- peroxisome proliferator-activated receptor-gamma coactivator
- reactive oxygen species
- ribonucleic acid
- suppressor of cytokine signaling
- signal transducer and activator of transcription
- mitochondrial transcriptional factor A
- triphenyltetrazolium chloride
- terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling
- Received September 19, 2011.
- Revision received October 19, 2011.
- Accepted October 20, 2011.
- American College of Cardiology Foundation
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