Endogenous interleukin-22 prevents cardiac rupture after myocardial infarction in mice.

Myocardial infarction (MI) can result in fatal myocardial rupture or heart failure due to adverse remodeling and dysfunction of the left ventricle. Although recent studies have shown that exogenous interleukin (IL)-22 shows cardioprotective effect after MI, the pathophysiological significance of endogenous IL-22 is unknown. In this study, we investigated the role of endogenous IL-22 in a mouse model of MI. We produced MI model by permanent ligation of the left coronary artery in wild-type (WT) and IL-22 knock-out (KO) mice. The post-MI survival rate was significantly worse in IL-22KO mice than in WT mice due to a higher rate of cardiac rupture. Although IL-22KO mice exhibited a significantly greater infarct size than WT mice, there was no significant difference in left ventricular geometry or function between WT and IL-22KO mice. IL-22KO mice showed increase in infiltrating macrophages and myofibroblasts, and altered expression pattern of inflammation- and extracellular matrix (ECM)-related genes after MI. While IL-22KO mice showed no obvious changes in cardiac morphology or function before MI, expressions of matrix metalloproteinase (MMP)-2 and MMP-9 were increased, whereas that of tissue inhibitor of MMPs (TIMP)-3 was decreased in cardiac tissue. Protein expression of IL-22 receptor complex, IL-22 receptor alpha 1 (IL-22R1) and IL-10 receptor beta (IL-10RB), were increased in cardiac tissue 3 days after MI, regardless of the genotype. We propose that endogenous IL-22 plays an important role in preventing cardiac rupture after MI, possibly by regulating inflammation and ECM metabolism.

Multidisciplinary Team-Based Palliative Care for Heart Failure and Food Intake at the End of Life.

Traditionally, patients with end-stage heart failure (HF) have rarely been involved in end-of-life care (EOLC) discussions in Japan. The purpose of this study was to examine the impact of HF-specific palliative care team (HF-PCT) activities on EOLC discussions with patients, HF therapy and care, and food intake at the end of life. We retrospectively analyzed 52 consecutive patients with HF (mean age, 70 ± 15 years; 42% female) who died at our hospital between May 2013 and July 2020 and divided them into two groups: before (Era 1, n = 19) and after (Era 2, n = 33) the initiation of HF-PCT activities in June 2015. Compared to Era 1, Era 2 showed a decrease in invasive procedures, an increase in opioid and non-intubating sedative use for symptom relief, improved quality of meals at the end of life, and an increase in participation in EOLC discussions. The administration of artificial nutrition in the final three days was associated with non-ischemic cardiomyopathy etiology, the number of previous hospitalizations for HF, and multidisciplinary EOLC discussion support. HF-PCT activities may provide an opportunity to discuss EOLC with patients, reduce the burden of physical and psychological symptoms, and shift the goals of end-of-life nutritional intake to ensure comfort and quality of life.

SOCS3 deficiency in cardiomyocytes elevates sensitivity of ischemic preconditioning that synergistically ameliorates myocardial ischemia reperfusion injury.

Ischemic preconditioning (IPC) is the most powerful endogenous cardioprotective form of cellular adaptation. However, the inhibitory or augmenting mechanism underlying cardioprotection via IPC remains largely unknown. Suppressor of cytokine signaling-3 (SOCS3) is a cytokine-inducible potent negative feedback regulator of the signal transducer and activator of transcription-3 (STAT3) signaling pathway. Here, we aimed to determine whether cardiac SOCS3 deficiency and IPC would synergistically reduce infarct size after myocardial ischemia reperfusion injury. We evaluated STAT3 activation and SOCS3 induction after ischemic conditioning (IC) using western blot analysis and real-time PCR, and found that myocardial IC alone transiently activated myocardial STAT3 and correspondingly induced SOCS3 expression in wild-type mice. Compared with wild-type mice, cardiac-specific SOCS3 knockout (SOCS3-CKO) mice showed significantly greater and more sustained IC-induced STAT3 activation. Following ischemia reperfusion, IPC substantially reduced myocardial infarct size and significantly enhanced STAT3 phosphorylation in SOCS3-CKO mice compared to in wild-type mice. Real-time PCR array analysis revealed that SOCS3-CKO mice after IC exhibited significantly increased expressions of several anti-apoptotic genes and SAFE pathway-related genes. Moreover, real-time PCR analysis revealed that myocardial IC alone rapidly induced expression of the STAT3-activating cytokine erythropoietin in the kidney at 1 h post-IC. We also found that the circulating erythropoietin level was promptly increased at 1 h after myocardial IC. Myocardial SOCS3 deficiency and IPC exert synergistic effects in the prevention of myocardial injury after ischemia reperfusion. Our present results suggest that myocardial SOCS3 is a potent inhibitor of IPC-induced cardioprotection, and that myocardial SOCS3 inhibition augment IPC-mediated cardioprotection during ischemia reperfusion injury.

Interleukin-22 Directly Activates Myocardial STAT3 (Signal Transducer and Activator of Transcription-3) Signaling Pathway and Prevents Myocardial Ischemia Reperfusion Injury.

BACKGROUND Interleukin (IL)-22, a member of the IL-10 cytokine family, is the only known cytokine that is secreted by immune cells but does not target immune cells; it mainly targets epithelial cells. In this study, we aimed to determine whether IL-22 administration could activate the myocardial STAT3 (signal transducer and activator of transcription-3) signaling pathway, and thus prevent myocardial injury, in a mouse model of ischemia reperfusion injury. METHODS AND RESULTS We evaluated the STAT3 activation after IL-22 injection by Western blot analysis and immunostaining for phosphorylated STAT3 in the heart and found that STAT3 activation in heart tissue rapidly peaked after IL-22 injection. Coimmunostaining of phosphorylated STAT3 and α-actinin revealed that STAT3 activation occurred in cardiomyocytes after IL-22 administration. In heart tissue from intact mice, real-time PCR demonstrated significant expression of IL-22 receptor subunit 1, and coimmunostaining of IL-22 receptor subunit 1 and α-actinin showed IL-22 receptor subunit 1 expression in cardiomyocytes. In cultured cardiomyocytes, IL-22 activated STAT3, and we detected IL-22 receptor subunit 1 expression. Overall, these results indicated that IL-22 directly activated the myocardial IL-22-receptor subunit 1-STAT3 signaling pathway. Following ischemia reperfusion, compared with PBS-treated mice, IL-22-treated mice exhibited a significantly reduced infarct size, significantly reduced myocardial apoptosis, and significantly enhanced phosphorylated STAT3 expression. Moreover, heart tissue from IL-22-treated mice exhibited a significantly reduced expression ratio of phosphorylated p53 to p53. CONCLUSIONS Our present findings suggest that IL-22 directly activated the myocardial STAT3 signaling pathway and acted as a cardioprotective cytokine to ameliorate acute myocardial infarction after ischemia reperfusion.

Genetic Deletion of Socs3 in Smooth Muscle Cells Ameliorates Aortic Dissection in Mice.

Aortic dissection (AD) is the acute destruction of aortic wall and is reportedly induced by inflammatory response. Here we investigated the role of smooth muscle Socs3 (a negative regulator of Janus kinases/signal transducer and activator of transcription signaling) in AD pathogenesis using a mouse model generated via ß-aminopropionitrile and angiotensin II infusion. Socs3 deletion specifically in smooth muscle cells yielded a chronic inflammatory response of the aortic wall, which was associated with increased fibroblasts, reinforced aortic tensile strength, and less-severe tissue destruction. Although an acute inflammatory response is detrimental in AD, smooth muscle-regulated inflammatory response seemed protective against AD.

High Salt Intake Worsens Aortic Dissection in Mice: Involvement of IL (Interleukin)-17A-Dependent ECM (Extracellular Matrix) Metabolism.

OBJECTIVE: Aortic dissection (AD) is a fatal disease that occurs suddenly without preceding clinical signs or symptoms. Although high salt intake is a proposed risk factor for cardiovascular diseases, the relationship between AD and high salt intake has not been clarified. We examined the effect of high-salt challenge on a mouse AD model. Approach and Results: AD was induced in male mice by continuous infusion of ß-aminopropionitrile and Ang II (angiotensin II). High-salt challenge exacerbated aortic wall destruction in AD. Deletion of Il17a (IL-17KO [IL (interleukin)-17A knockout]) did not affect the AD phenotype at baseline, but it abolished the high salt-induced worsening of the aortic destruction. Unexpectedly, aortas of IL-17KO mice exhibited global changes in ECM (extracellular matrix)-related genes without alteration of proinflammatory genes, altered architecture of collagen fibers, and reduced stiffness before AD induction. The aortas of IL-17KO mice were less sensitive to AD-inducing stimuli, as shown by the induction of phenotypic modulation markers SMemb and vimentin, suggesting a reduced stress response. The aortas of IL-17KO mice had a higher population of smooth muscle cells with nuclear-localized phosphorylated Smad2, indicative of TGFß (transforming growth factor-beta) signal activation. Consistently, pretreatment of smooth muscle cells in culture with IL-17A blunted the activation of Smad2 by TGFß1. CONCLUSIONS: These findings indicate that high salt intake has a worsening effect on AD in the context of high aortic wall stiffness, which is under the control of IL-17A through ECM metabolism. Therefore, salt restriction may represent a low-cost and practical way to reduce AD risk.

Role of Macrophage Socs3 in the Pathogenesis of Aortic Dissection.

BACKGROUND: Aortic dissection (AD) is a life-threatening medical emergency caused by the abrupt destruction of the intimomedial layer of the aortic walls. Given that previous studies have reported the involvement of proinflammatory cytokine interleukin-6 in AD pathogenesis, we investigated the role of signal transduction and activator of transcription 3 signaling, a downstream pathway of interleukin-6 in macrophages in pathogenesis of AD. METHODS AND RESULTS: We characterized the pathological and molecular events triggered by aortic stress, which can lead to AD. Aortic stress on the suprarenal aorta because of infrarenal aorta stiffening and angiotensin II infusion for 1 week caused focal medial rupture at the branching point of the celiac trunk and superior mesenteric artery. This focal medial rupture healed in 6 weeks in wild-type (WT) mice, but progressed to AD in mice with macrophage-specific deletion of Socs3 gene (mSocs3-KO). mSocs3-KO mice showed premature activation of cell proliferation, an inflammatory response, and skewed differentiation of macrophages toward the tissue-destructive phenotype. Concomitantly, they showed aberrant phenotypic modulation of smooth muscle cells and transforming growth factor beta signaling, which are likely to participate in tissue repair. Human AD samples revealed signal transduction and activator of transcription 3 activation in adventitial macrophages adjacent to the site of tissue destruction. CONCLUSIONS: These findings suggest that AD development is preceded by focal medial rupture, in which macrophage Socs3 maintains proper inflammatory response and differentiation of SMCs, thus promoting fibrotic healing to prevent tissue destruction and AD development. Understanding the sequence of the pathological and molecular events preceding AD development will help predict and prevent AD development and progression.

Disturbance of cardiac gene expression and cardiomyocyte structure predisposes Mecp2-null mice to arrhythmias.

Methyl-CpG-binding protein 2 (MeCP2) is an epigenetic regulator of gene expression that is essential for normal brain development. Mutations in MeCP2 lead to disrupted neuronal function and can cause Rett syndrome (RTT), a neurodevelopmental disorder. Previous studies reported cardiac dysfunction, including arrhythmias in both RTT patients and animal models of RTT. In addition, recent studies indicate that MeCP2 may be involved in cardiac development and dysfunction, but its role in the developing and adult heart remains unknown. In this study, we found that Mecp2-null ESCs could differentiate into cardiomyocytes, but the development and further differentiation of cardiovascular progenitors were significantly affected in MeCP2 deficiency. In addition, we revealed that loss of MeCP2 led to dysregulation of endogenous cardiac genes and myocardial structural alterations, although Mecp2-null mice did not exhibit obvious cardiac functional abnormalities. Furthermore, we detected methylation of the CpG islands in the Tbx5 locus, and showed that MeCP2 could target these sequences. Taken together, these results suggest that MeCP2 is an important regulator of the gene-expression program responsible for maintaining normal cardiac development and cardiomyocyte structure.

Cardiac-Specific SOCS3 Deletion Prevents In Vivo Myocardial Ischemia Reperfusion Injury through Sustained Activation of Cardioprotective Signaling Molecules.

Myocardial ischemia reperfusion injury (IRI) adversely affects cardiac performance and the prognosis of patients with acute myocardial infarction. Although myocardial signal transducer and activator of transcription (STAT) 3 is potently cardioprotective during IRI, the inhibitory mechanism responsible for its activation is largely unknown. The present study aimed to investigate the role of the myocardial suppressor of cytokine signaling (SOCS)-3, an intrinsic negative feedback regulator of the Janus kinase (JAK)-STAT signaling pathway, in the development of myocardial IRI. Myocardial IRI was induced in mice by ligating the left anterior descending coronary artery for 1 h, followed by different reperfusion times. One hour after reperfusion, the rapid expression of JAK-STAT-activating cytokines was observed. We precisely evaluated the phosphorylation of cardioprotective signaling molecules and the expression of SOCS3 during IRI and then induced myocardial IRI in wild-type and cardiac-specific SOCS3 knockout mice (SOCS3-CKO). The activation of STAT3, AKT, and ERK1/2 rapidly peaked and promptly decreased during IRI. This decrease correlated with the induction of SOCS3 expression up to 24 h after IRI in wild-type mice. The infarct size 24 h after reperfusion was significantly reduced in SOCS3-CKO compared with wild-type mice. In SOCS3-CKO mice, STAT3, AKT, and ERK1/2 phosphorylation was sustained, myocardial apoptosis was prevented, and the expression of anti-apoptotic Bcl-2 family member myeloid cell leukemia-1 (Mcl-1) was augmented. Cardiac-specific SOCS3 deletion led to the sustained activation of cardioprotective signaling molecules including and prevented myocardial apoptosis and injury during IRI. Our findings suggest that SOCS3 may represent a key factor that exacerbates the development of myocardial IRI.

Renal Nerve-Mediated Erythropoietin Release Confers Cardioprotection During Remote Ischemic Preconditioning.

BACKGROUND: Remote ischemic preconditioning (RIPC) induced by transient limb ischemia is a powerful innate mechanism of cardioprotection against ischemia. Several described mechanisms explain how RIPC may act through neural pathways or humoral factors; however, the mechanistic pathway linking the remote organ to the heart has not yet been fully elucidated. This study aimed to investigate the mechanisms underlying the RIPC-induced production of Janus kinase (JAK)-signal transducer and activator of the transcription (STAT)-activating cytokines and cardioprotection by using mouse and human models of RIPC. METHODS AND RESULTS: Screened circulating cardioprotective JAK-STAT-activating cytokines in mice unexpectedly revealed increased serum erythropoietin (EPO) levels after RIP induced by transient ischemia. In mice, RIPC rapidly upregulated EPO mRNA and its main transcriptional factor, hypoxia-inducible factor-1α (HIF1α), in the kidney. Laser Doppler blood flowmetry revealed a prompt reduction of renal blood flow (RBF) after RIPC. RIPC activated cardioprotective signaling pathways and the anti-apoptotic Bcl-xL pathway in the heart, and reduced infarct size. In mice, these effects were abolished by administration of an EPO-neutralizing antibody. Renal nerve denervation also abolished RIPC-induced RBF reduction, EPO production, and cardioprotection. In humans, transient limb ischemia of the upper arm reduced RBF and increased serum EPO levels. CONCLUSIONS: Based on the present data, we propose a novel RIPC mechanism in which inhibition of infarct size by RIPC is produced through the renal nerve-mediated reduction of RBF associated with activation of the HIF1α-EPO pathway.

ETS transcription factor ETV2 directly converts human fibroblasts into functional endothelial cells.

Transplantation of endothelial cells (ECs) is a promising therapeutic approach for ischemic disorders. In addition, the generation of ECs has become increasingly important for providing vascular plexus to regenerated organs, such as the liver. Although many attempts have been made to generate ECs from pluripotent stem cells and nonvascular cells, the minimum number of transcription factors that specialize in directly inducing vascular ECs remains undefined. Here, by screening 18 transcription factors that are important for both endothelial and hematopoietic development, we demonstrate that ets variant 2 (ETV2) alone directly converts primary human adult skin fibroblasts into functional vascular endothelial cells (ETVECs). In coordination with endogenous FOXC2 in fibroblasts, transduced ETV2 elicits expression of multiple key endothelial development factors, including FLI1, ERG, and TAL1, and induces expression of endothelial functional molecules, including EGFL7 and von Willebrand factor. Consequently, ETVECs exhibits EC characteristics in vitro and forms mature functional vasculature in Matrigel plugs transplanted in NOD SCID mice. Furthermore, ETVECs significantly improve blood flow recovery in a hind limb ischemic model using BALB/c-nu mice. Our study indicates that the creation of ETVECs provides further understanding of human EC development induced by ETV2.

Omentin prevents myocardial ischemic injury through AMP-activated protein kinase- and Akt-dependent mechanisms.

OBJECTIVES: This study examined the impact of omentin on myocardial injury in a mouse model of ischemia/reperfusion (I/R) and explored its underlying mechanisms. BACKGROUND: Obesity is a major risk factor for ischemic heart disease. Omentin is a circulating adipokine that is down-regulated by obesity. METHODS: In patients who underwent successful reperfusion treatment after acute myocardial infarction, cardiac function and perfusion defect were assessed by using scintigraphic images. Mice were subjected to myocardial ischemia followed by reperfusion. RESULTS: This study found that high levels of plasma omentin were associated with improvement of heart damage and function after reperfusion therapy in patients with acute myocardial infarction. Systemic administration of human omentin to mice led to a reduction in myocardial infarct size and apoptosis after I/R, which was accompanied by enhanced phosphorylation of AMP-activated protein kinase (AMPK) and Akt in the ischemic heart. Fat-specific overexpression of human omentin also resulted in reduction of infarct size after I/R. Blockade of AMPK or Akt activity reversed omentin-induced inhibition of myocardial ischemic damage and apoptosis in mice. In cultured cardiomyocytes, omentin suppressed hypoxia/reoxygenation-induced apoptosis, which was blocked by inactivation of AMPK or Akt. CONCLUSIONS: Our data indicate that omentin functions as an adipokine that ameliorates acute ischemic injury in the heart by suppressing myocyte apoptosis through both AMPK- and Akt-dependent mechanisms.

Protective role of JAK/STAT signaling against renal fibrosis in mice with unilateral ureteral obstruction.

Inflammation is involved in renal fibrosis, a final common pathway for kidney diseases. To clarify how JAK/STAT/SOCS system was involved in renal fibrosis, UUO was induced in BALB/c or SOCS3(+/-) mice in the presence or absence of JAK inhibitor-incorporated nanoparticle (pyridine6-PGLA). UUO increased pSTAT3 and subsequently elevated SOCS3 levels in the obstructed kidneys. pSTAT3 levels were further increased in SOCS3(+/-) mice. UUO-induced renal fibrosis was markedly suppressed in SOCS3(+/-) mice, while it was aggravated by pre-treatment with pyridine6-PGLA. Although there were no differences in renal mRNA levels of TGF-ß and collagens between wild and SOCS3(+/-) mice, MMP-2 activity was enhanced in SOCS3(+/-) UUO mice. Activated MMP-2 was completely suppressed by pyridine6-PGLA-pre-treatment. TNF-α one of JAK/STAT activators, increased pSTAT3 levels and subsequently induced MMP-2 activation in proximal tubular cells. These results suggest that JAK/STAT3 signaling may play a role in repair process of renal fibrosis in UUO partly via MMP-2 activation.

Transient reduction and activation of circulating dendritic cells in patients with acute myocardial infarction.

BACKGROUND: Dendritic cells (DCs) are highly potent professional antigen-presenting cells that play a central role in initiating the primary immune response. Accumulating evidence suggests that immune-mediated inflammation plays an important role in the pathophysiology of AMI, but the mechanism that triggers such immune responses is unknown. METHODS: Using multi-color flow-cytometry, we determined the numbers of circulating myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) in patients with AMI (n = 26) or stable angina pectoris (SAP) (n = 19), and in age-matched control subjects (n = 19). The DC activation markers CD40 and CD83 were also measured. RESULTS: On admission, circulating mDC and pDC counts were significantly lower in AMI patients compared to control subjects and SAP patients (mDC, P < 0.01; pDC, P < 0.05). The activation markers of mDCs in AMI patients were significantly higher and returned to the levels of control subjects or SAP patients 3 days after AMI (mDC, P < 0.05; pDC, P < 0.05). Reductions of circulating mDC and pDC numbers were restored 7 days after the onset of AMI. Furthermore, we found that the recovery of the circulating DC numbers 14 days after AMI was correlated with the alterations of creatine kinase-MB (CK-MB) (mDC, r = 0.48, P < 0.05; pDC, r=0.52, P < 0.01) and brain natriuretic peptide (BNP) (mDC, r = 0.53, P < 0.01; pDC, r = 0.51, P < 0.01). CONCLUSION: Our findings suggest that the transient reduction and activation of circulating DCs may play important roles in the pathophysiology of myocardial injury after AMI.

Cardiomyocyte-specific transgenic expression of lysyl oxidase-like protein-1 induces cardiac hypertrophy in mice.

Lysyl oxidase (LOX) and LOX-like protein-1 (LOXL-1) are extracellular matrix-embedded amine oxidases that have critical roles in the cross-linking of collagen and elastin. LOX family proteins are abundantly expressed in the remodeled heart of animals and humans and are implicated in cardiac fibrosis; however, their role in cardiac hypertrophy is unknown. In this study, in vitro stimulation with hypertrophic agonists significantly increased LOXL-1 expression, LOX enzyme activity and [(3)H] leucine incorporation in neonatal rat cardiomyocytes. A LOX inhibitor, beta-aminopropionitrile (BAPN), inhibited agonist-induced leucine incorporation in cardiomyocytes in vitro, suggesting the involvement of LOXL-1 in cardiomyocyte hypertrophy. Abdominal aortic constriction in rats produced left ventricular hypertrophy in parallel with LOXL-1 mRNA upregulation. And BAPN administration significantly inhibited angiotensin II-induced cardiac hypertrophy in vivo. These results suggest a role of LOXL-1 in cardiac hypertrophy in vivo. We generated transgenic mice with cardiomyocyte-specific expression of LOXL-1. LOXL-1 transgenic mice pups were born normally and grew to adulthood without increased mortality; these mice exhibited a greater left ventricle to body weight ratio, larger myocyte diameter, and more brain natriuretic peptide expression than their wild-type littermates. Echocardiography revealed that the LOXL-1 transgenic mice also had greater wall thickness with preserved cardiac contraction. Our results indicate a possible fundamental role of LOXL-1 in cardiac hypertrophy.

SOCS, Inflammation, and Autoimmunity.

Cytokines play essential roles in innate and adaptive immunity. However, excess cytokines or dysregulation of cytokine signaling will cause a variety of diseases, including allergies, autoimmune diseases, inflammation, and cancer. Most cytokines utilize the so-called Janus kinase-signal transducers and activators of transcription pathway. This pathway is negatively regulated by various mechanisms including suppressors of cytokine signaling (SOCS) proteins. SOCS proteins bind to JAK or cytokine receptors, thereby suppressing further signaling events. Especially, suppressor of cytokine signaling-1 (SOCS1) and SOCS3 are strong inhibitors of JAKs, because these two contain kinase inhibitory region at the N-terminus. Studies using conditional knockout mice have shown that SOCS proteins are key physiological as well as pathological regulators of immune homeostasis. Recent studies have also demonstrated that SOCS1 and SOCS3 are important regulators of helper T cell differentiation and functions. This review focuses on the roles of SOCS1 and SOCS3 in T cell mediated inflammatory diseases.

Cardiac-specific deletion of SOCS-3 prevents development of left ventricular remodeling after acute myocardial infarction.

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.

JAK's SOCS: a mechanism of inhibition.

SOCS1 and SOCS3 are specific inhibitors for JAK tyrosine kinases. In this issue of Immunity, Babon et al. (2012) discovered the inhibition mechanism of SOCS3 by employing nuclear magnetic resonance and classical enzyme kinetics.