Cardiac-Specific Deletion of SOCS-3 Prevents Development of Left Ventricular Remodeling After Acute Myocardial Infarction

Oba, Toyoharu; Yasukawa, Hideo; Hoshijima, Masahiko; Sasaki, Ken; Futamata, Nobuyoshi; Fukui, Daisuke; Mawatari, Ken‐ichi; Nagata, T.; Kyogoku, Sachiko; Ohshima, Hideki; Minami, Tetsuro; Nakamura, Kei‐ichiro; Kang, Dongchon; Yajima, Toshitaka; Knowlton, Kirk U.; Imaizumi, Tsutomu

doi:10.1016/j.jacc.2011.10.887

Cited by 62 publications

(75 citation statements)

References 46 publications

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“…Overexpression of a dominant-negative Stat3 3 days before apical resection significantly inhibits muscle regeneration and results in extensive scarring at 30 dpi, suggesting an anti-remodeling role of Jak/Stat signaling similar to that observed in the mammalian heart after MI [41,42]. Concomitantly, cell cycle re-entry of CMs is also inhibited at 7 dpi in the same experiment [40].…”

Section: Do All Zebrafish Cardiomyocytes Proliferate and Contribute Tsupporting

confidence: 61%

Zebrafish as a Model for Studying Cardiac Regeneration

Weidinger

2014

Curr Pathobiol Rep

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Heart failure caused by cardiomyocyte loss after ischemic tissue damage is a leading cause of death worldwide. Although adult mammalian cardiomyocytes are able to proliferate during normal aging and after infarction, they do so at insufficient rates for effective cardiac regeneration. Likewise, none of several described cardiac stem cell populations appear to form significant numbers of cardiomyocytes in ischemic hearts. Thus, adult mammals cannot regenerate heart injuries. Zebrafish, on the contrary, are able to regenerate multiple organs including amputated fins, lesioned brain, retina, spinal cord as well as the heart. In response to injury, spared zebrafish cardiomyocytes reenter the cell cycle, proliferate and form new cardiomyocytes robustly, resulting in full morphological and functional recovery. Since zebrafish heart regeneration was first described about a decade ago, this model has significantly improved our knowledge about the underlying mechanisms of natural heart regeneration. Here, we describe different heart injury techniques and review our current knowledge about cellular and molecular mechanisms of regeneration, with a focus on factors regulating cardiomyocyte proliferation.

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Section: Do All Zebrafish Cardiomyocytes Proliferate and Contribute Tsupporting

confidence: 61%

Zebrafish as a Model for Studying Cardiac Regeneration

Weidinger

2014

Curr Pathobiol Rep

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“…28 At 2 h after left coronary artery occlusion, the area at risk and initial infarct area were determined by perfusion with 5% Evans blue dye and subsequent incubation with triphenyltetrazolium chloride, as previously described. 28 …”

Section: Modelmentioning

confidence: 99%

“…Western blot analysis was performed as described previously, 28 using antibodies raised against phosphorylated STAT3, phosphorylated AKT, phosphorylated ERK1/2, Bcl-xL, Bax (New England BioLabs), HIF1α (Abcam), and GAPDH. For HIF1α western blotting, we prepared negative and positive controls of HIF1α by rendering human astrocytes under normoxic and hypoxic conditions, respectively.…”

Section: Western Blot Analysismentioning

confidence: 99%

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

Oba

Yasukawa

Nagata

et al. 2015

Circ J

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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. 1558OBA T et al. Hypoxia Inducible Factor-1α (HIF1α) Immunohistochemical StainingMouse kidneys were harvested 1 h after RIPC. Embedded sections were deparaffinized, and endogenous peroxidase activity was inhibited by treating the sections with 0.3% H2O2 in PBS for 10 min. After several washes with PBS, the sections were incubated for 20 min with blocking solution (Jackson ImmunoResearch) to block non-specific binding, followed by overnight incubation at 4°C with the purified anti-hypoxia inducible factor-1α (HIF1α) antibody (Abcam). Subsequently, the sections were incubated with an alkaline phosphatase-conjugated goat anti-rabbit IgG antibody for 30 min. Signal amplification was achieved by incubating the slides for 30 min with Vectastain Elite Avidin-Biotin Complex solution (Vectastain ABC Kit, Vector), followed by incubation with Vectastain diaminobenzidine solution as the chromagen marker (Dako). 28 For a negative staining control, goat serum was used in place of the HIF1α antibody. Renal Blood Flow (RBF) MonitoringMouse RBF was measured at 0 min and every 2 min during and after RIPC induction, using a laser Doppler blood flow imager (Laser Doppler Perfusion Imager System, moorLDI TMMark 2, Moor Instruments). Before RBF scanning in the right kidney, mice were placed on a heating pad at 37°C to minimize temperature variations. In control mice, a sham...

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“…Expression values for each gene were normalized to 18S ribosomal RNA (TaqMan ribosomal RNA control reagents; Applied Biosystems). 24 …”

Section: Rna Extraction and Real-time Pcrmentioning

confidence: 99%

“…Mice were anesthetized with isoflurane and subjected to echocardiography as previously described. [22][23][24] Recording was performed as described previously. [22][23][24] …”

Section: Echocardiographymentioning

confidence: 99%

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

et al. 2012

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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.

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Cardiac-Specific Deletion of SOCS-3 Prevents Development of Left Ventricular Remodeling After Acute Myocardial Infarction

Abstract: 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.

Cited by 62 publications

References 46 publications

Zebrafish as a Model for Studying Cardiac Regeneration

Zebrafish as a Model for Studying Cardiac Regeneration

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

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

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