Abstract 11985: C1q / tnf-Related Protein 9 Protects Against Acute Myocardial Injury

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Takahiro Kambara ◽  
Rei Shibata ◽  
Koji Ohashi ◽  
Yuusuke Joki ◽  
Satoko Hayakawa ◽  
...  
Keyword(s):  
Cardiac Myocytes ◽  
Inflammatory Cytokines ◽  
Ischemia Reperfusion ◽  
Dominant Negative ◽  
Dominant Negative Mutant ◽  
Mutant Form ◽  
Related Protein ◽  
Increased Risk ◽  
Tnf Α ◽  
Negative Mutant

Background: Obesity-related disorders are associated with an increased risk for cardiovascular disease. C1q/TNF-related protein (CTRP) 9 is an anti-diabetic adipokine that is downregulated in obese mice. Recently, we have reported that CTRP9 prevents adverse vascular remodeling in response to injury. Here, we investigated the effect of CTRP9 on acute cardiac injury with loss-of-function genetic manipulations. Methods and Results: CTRP9-deficient (CTRP9-KO) mice at the age of 12 weeks were indistinguishable from Wild-type (WT) mice under basal conditions. CTRP9-KO mice showed increased myocardial infarct size and elevated expression of inflammatory cytokines including TNF-α and IL-6 in ischemic heart following ischemia-reperfusion compared with WT mice. CTRP9-KO mice also had exacerbated contractile left ventricle (LV) dysfunction and increased myocardial expression of inflammatory cytokines following intraperitoneal injection of lipopolysaccharide (LPS) compared with WT mice. Conversely, systemic delivery of an adenoviral vector expressing CTRP9 (Ad-CTRP9) attenuated inflammatory responses to myocardial ischemia-reperfusion or LPS administration in WT mice. In cultured cardiac myocytes, treatment with CTRP9 protein suppressed LPS-stimulated expression of TNF-α and IL-6 with an accompanying reduction of NFkB phosphorylation. Treatment of cardiac myocytes with CTRP9 enhanced AMPK phosphorylation, and transduction with dominant-negative mutant form of AMPK reversed the suppressive effect of CTRP9 on TNF-α and IL-6 expression. Furthermore, systemic administration of Ad-CTRP9 improved LPS-induced cardiac dysfunction in WT mice but not in muscle-specific transgenic mice expressing dominant-negative mutant form of AMPK. Conclusions: These findings suggest that CTRP9 protects against acute cardiac damage in response to pathological stimuli by suppressing inflammatory reactions through AMPK-dependent mechanisms.

TNF-α induces protein synthesis through PI3-kinase-Akt/PKB pathway in cardiac myocytes

2001 ◽  
Vol 280 (4) ◽  
pp. H1861-H1868 ◽  
Author(s):  
Eiji Hiraoka ◽  
Seinosuke Kawashima ◽  
Tomosaburo Takahashi ◽  
Yoshiyuki Rikitake ◽  
Tadahiro Kitamura ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Cardiac Myocytes ◽  
Specific Inhibitor ◽  
Pi3 Kinase ◽  
Dominant Negative ◽  
Neonatal Rat ◽  
Dominant Negative Mutant ◽  
Tnf Α ◽  
Negative Mutant ◽  
Stimulation Of

The activation of phosphatidylinositol (PI) 3-kinase and Akt/protein kinase B (PKB) by tumor necrosis factor (TNF)-α and their roles on stimulation of protein synthesis were investigated in cultured neonatal rat cardiac myocytes. Treatment of cells with TNF-α resulted in enlargement of cell surface area and stimulation of protein synthesis without affecting myocyte viability. TNF-α induced marked activation of PI3-kinase and Akt/PKB, and the activation of PI3-kinase and Akt/PKB was rapid (maximal at 10 and 15 min, respectively) and concentration dependent. Akt/PKB activation by TNF-α was inhibited by a PI3-kinase-specific inhibitor LY-294002 and adenovirus-mediated expression of a dominant negative mutant of PI3-kinase, indicating that TNF-α activates Akt/PKB through PI3-kinase activation. Furthermore, TNF-α-induced protein synthesis was inhibited by pretreatment with LY-294002 and expression of a dominant negative mutant of PI3-kinase or Akt/PKB. These results indicate that activation of the PI3-kinase-Akt/PKB pathway plays an essential role in protein synthesis induced by TNF-α in cardiac myocytes.

scholarly journals Inhibition of transcription-regulating properties of nonstructural protein 1 (NS1) of parvovirus minute virus of mice by a dominant-negative mutant form of NS1

2001 ◽  
Vol 82 (8) ◽  
pp. 1929-1934 ◽  
Author(s):  
Laurent Deleu ◽  
Aurora Pujol ◽  
Jürg P. F. Nüesch ◽  
Jean Rommelaere
Keyword(s):  
Nonstructural Protein ◽  
Dominant Negative ◽  
Dominant Negative Mutant ◽  
Mutant Form ◽  
Viral Dna ◽  
Minute Virus Of Mice ◽  
Viral Dna Replication ◽  
Nonstructural Protein 1 ◽  
Minute Virus ◽  
Negative Mutant

Nonstructural protein 1 (NS1) of minute virus of mice is involved in viral DNA replication, transcriptional regulation and cytotoxic action in the host cell. Viral DNA replication is dependent on the ability of NS1 to form homo-oligomers. To investigate whether oligomerization is required for NS1 transcriptional activities, a functionally impaired mutant derivative of NS1 that was able to interact with the wild-type (wt) protein and inhibit its activity in a dominant-negative manner was designed. This mutant provided evidence that transactivation of the parvoviral P38 promoter and transinhibition of a heterologous promoter by NS1 were both affected by the co-expression of the wt and the dominant-negative mutant form of NS1. These results indicate that additional functions of NS1, involved in promoter regulation, require oligomer formation.

scholarly journals C1q/Tumor Necrosis Factor-Related Protein 9 Protects against Acute Myocardial Injury through an Adiponectin Receptor I-AMPK-Dependent Mechanism

2015 ◽  
Vol 35 (12) ◽  
pp. 2173-2185 ◽  
Author(s):  
Takahiro Kambara ◽  
Rei Shibata ◽  
Koji Ohashi ◽  
Kazuhiro Matsuo ◽  
Mizuho Hiramatsu-Ito ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Myocardial Infarct ◽  
Dominant Negative ◽  
Adiponectin Receptor ◽  
Dominant Negative Mutant ◽  
Myocardial Infarct Size ◽  
Mutant Form ◽  
Related Protein ◽  
Necrosis Factor

Obesity is a risk factor for cardiovascular disease. C1q/tumor necrosis factor-related protein 9 (CTRP9) is an adipokine that is downregulated by obesity. We investigated the role of CTRP9 in cardiac injury with loss-of-function genetic manipulations and defined the receptor-mediated signaling pathway downstream of this adipokine. CTRP9-knockout (CTRP9-KO) mice at the age of 12 weeks were indistinguishable from wild-type (WT) mice under basal conditions. CTRP9-KO mice had exacerbated contractile left ventricle dysfunction following intraperitoneal injection of lipopolysaccharide (LPS) compared to WT mice. Administration of LPS to CTRP9-KO mice also resulted in increased expression of proinflammatory cytokines and oxidative stress markers in the heart compared to WT mice. Likewise, CTRP9-KO mice showed increased myocardial infarct size and elevated expression of inflammatory mediators in ischemic heart following ischemia and reperfusion compared to WT mice. Treatment of cardiac myocytes with CTRP9 protein led to suppression of LPS-induced expression of proinflammatory genes, which was reversed by blockade of AMPK or ablation of adiponectin receptor I (AdipoR1). Systemic delivery of CTRP9 attenuated LPS-induced cardiac dysfunction in WT mice but not in muscle-specific transgenic mice expressing dominant-negative mutant form of AMPK or in AdipoR1-knockout mice. CTRP9 protects against acute cardiac damage in response to pathological stimuli by suppressing inflammatory reactions through AdipoR1/AMPK-dependent mechanisms.

scholarly journals Pathophysiological Remodeling of Mouse Cardiac Myocytes Expressing Dominant Negative Mutant of Neuron Restrictive Silencing Factor

2010 ◽  
Vol 74 (12) ◽  
pp. 2712-2719 ◽  
Author(s):  
Makoto Takano ◽  
Hideyuki Kinoshita ◽  
Takao Shioya ◽  
Masayuki Itoh ◽  
Kazuwa Nakao ◽  
...  
Keyword(s):  
Cardiac Myocytes ◽  
Dominant Negative ◽  
Dominant Negative Mutant ◽  
Negative Mutant

Phosphatidylinositol 3-kinase/Akt signaling mediates interleukin-32α induction in human pancreatic periacinar myofibroblasts

2008 ◽  
Vol 294 (3) ◽  
pp. G831-G838 ◽  
Author(s):  
Atsushi Nishida ◽  
Akira Andoh ◽  
Makoto Shioya ◽  
Shokei Kim-Mitsuyama ◽  
Atsushi Takayanagi ◽  
...  
Keyword(s):  
Western Blot ◽  
Mrna Expression ◽  
Inflammatory Responses ◽  
Dominant Negative ◽  
Dominant Negative Mutant ◽  
Mutant Form ◽  
Phosphatidylinositol 3 Kinase ◽  
Tnf Α ◽  
Ifn Γ ◽  
Phosphatidylinositol 3

Interleukin (IL)-32 is a recently described proinflammatory cytokine, characterized by the induction of nuclear factor (NF)-κB activation. We studied IL-32α expression in human pancreatic periacinar myofibroblasts, which play important roles in the regulation of extracellular matrix metabolism and inflammatory responses in the pancreas. IL-32α protein expression was evaluated by Western blot analyses, and IL-32α mRNA expression was analyzed by Northern blot and real-time PCR analyses. IL-32α mRNA was weakly expressed without a stimulus, and its expression was markedly enhanced by IL-1β, IFN-γ, and TNF-α. IL-1β, IFN-γ, and TNF-α enhanced intracellular accumulation of IL-32α protein, but IL-32α was not detected in supernatants. Each cytokine dose and time dependently induced IL-32α mRNA expression. An inhibitor of phosphatidylinositol 3-kinase (LY294002) significantly suppressed IL-1β-, IFN-γ-, and TNF-α-induced IL-32α mRNA expression, although MAPK inhibitors had no effect. Akt activation in response to these cytokines was confirmed by Western blot. Furthermore, LY294002 suppressed both IL-1β- and TNF-α-induced NF-κB activation and IL-1β-, TNF-α-, and IFN-γ-induced activated protein-1 (AP-1) activation. Blockade of NF-κB and AP-1 activation by an adenovirus expressing a stable mutant form of IκBα and a dominant negative mutant of c-Jun markedly suppressed IL-1β-, IFN-γ-, and/or TNF-α-induced IL-32α mRNA expression. Human pancreatic periacinar myofibroblasts expressed IL-32α in response to IL-1β, TNF-α, and IFN-γ. IL-32α mRNA expression is dependent on interactions between the phosphatidylinositol 3-kinase/Akt-pathway and the NF-κB/AP-1 system.

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