Takanobu Nagata

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.

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.

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.

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 [3H] 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.

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.

SOCS3: A novel therapeutic target for cardioprotection

The suppressors of cytokine signaling (SOCS) family of proteins are cytokine-inducible inhibitors of Janus kinase (JAK)-signal transducer and activator of the transcription (STAT) signaling pathways. Among the family, SOCS1 and SOCS3 potently suppress cytokine actions by inhibiting JAK kinase activities. The generation of mice lacking individual SOCS genes has been instrumental in defining the role of individual SOCS proteins in specific cytokine pathways in vivo; SOCS1 is an essential negative regulator of interferon-γ (IFNγ) and SOCS3 is an essential negative regulator of leukemia inhibitory factor (LIF). JAK-STAT3 activating cytokines have exhibited cardioprotective roles in the heart. The cardiac-specific deletion of SOCS3 enhances the activation of cardioprotective signaling pathways, inhibits myocardial apoptosis and fibrosis and results in the inhibition of left ventricular remodeling after myocardial infarction (MI). We propose that myocardial SOCS3 is a key determinant of left ventricular remodeling after MI, and SOCS3 may serve as a novel therapeutic target to prevent left ventricular remodeling after MI. In this review, we discuss the signaling pathways mediated by JAK-STAT and SOCS proteins and their roles in the development of myocardial injury under stress (e.g., pressure overload, viral infection and ischemia).The suppressors of cytokine signaling (SOCS) family of proteins are cytokine-inducible inhibitors of Janus kinase (JAK)-signal transducer and activator of the transcription (STAT) signaling pathways. Among the family, SOCS1 and SOCS3 potently suppress cytokine actions by inhibiting JAK kinase activities. The generation of mice lacking individual SOCS genes has been instrumental in defining the role of individual SOCS proteins in specific cytokine pathways in vivo; SOCS1 is an essential negative regulator of interferon-γ (IFNγ) and SOCS3 is an essential negative regulator of leukemia inhibitory factor (LIF). JAK-STAT3 activating cytokines have exhibited cardioprotective roles in the heart. The cardiac-specific deletion of SOCS3 enhances the activation of cardioprotective signaling pathways, inhibits myocardial apoptosis and fibrosis and results in the inhibition of left ventricular remodeling after myocardial infarction (MI). We propose that myocardial SOCS3 is a key determinant of left ventricular remodeling after MI, and SOCS3 may serve as a novel therapeutic target to prevent left ventricular remodeling after MI. In this review, we discuss the signaling pathways mediated by JAK-STAT and SOCS proteins and their roles in the development of myocardial injury under stress (e.g., pressure overload, viral infection and ischemia).

Screening for Fabry disease in patients with left ventricular hypertrophy

Kazutoshi Mawatari , Hideo Yasukawa ⁎, Toyoharu Oba , Takanobu Nagata , Tadayasu Togawa , Takahiro Tsukimura , Sachiko Kyogoku , Hideki Ohshima , Tomoko Minami , Yusuke Sugi , Hitoshi Sakuraba , Tsutomu Imaizumi a,b a Division of Cardiovascular Medicine, Department of Internal Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan b Cardiovascular Research Institute, Kurume University, 67 Asahi-machi, Kurume 830-0011, Japan c Department of Analytical Biochemistry, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan d Department of Clinical Genetics, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan

Prevalence of hypothyroidism in patients with hyponatremia: A retrospective cross-sectional study

Objective Hypothyroidism has been suggested to be an uncommon cause of hyponatremia. However, little is known about the prevalence of hypothyroidism in patients with different levels of hyponatremia. The objective of this study was to investigate the prevalence of hypothyroidism among patients with hyponatremia of varying severity while taking into consideration potential confounders associated with thyroid function. Methods All data on thyrotropin (TSH), free thyroxine (T4), and serum sodium (Na) levels were retrospectively collected from medical records at two Japanese tertiary hospitals. The main outcome measure was overt hypothyroidism, defined as TSH > 10.0 μIU/mL and free T4 < 1.01 ng/dL. Results Of 71,817 patients, 964 patients (1.3%) had overt hypothyroidism. The prevalence of overt hypothyroidism in each category of hyponatremia (Na ≥136, 130–135, and ≤129 mEq/L) was 1.2% (787/65,051), 2.4% (124/5,254) and 3.5% (53/1,512), respectively. A significant increase in prevalence was observed as the severity of hyponatremia increased (P < 0.001 for trend). Multivariate logistic regression with adjustment for age, sex, kidney function, and serum albumin level showed that the odds ratios for overt hypothyroidism increased with increasing severity of hyponatremia when compared with Na ≥ 136 mEq/L (130–135 mEq/L: 1.43, 95% confidence interval [CI], 1.15 to 1.78, P = 0.001; ≤129 mEq/L: 1.87, 95% CI, 1.32 to 2.63, P < 0.001; P< 0.001 for trend). Conclusion The prevalence of overt hypothyroidism was significantly higher as the severity of hyponatremia progressed, even after adjusting for potential confounders. Hypothyroidism should be differentiated in patients with hyponatremia.

Unstable Angina Pectoris in a 22-year-old Female Patient

Because of the protective effect of estrogen for atherosclerosis, the prevalence of acute coronary syndrome in women before menopause is low. We report a rare case of unstable angina in a young Japanese female who had a history of cigarette smoking and contraceptive use. Her coronary stenosis was successfully treated by percutaneous coronary intervention.