Antibody against interleukin-6 receptor attenuates left ventricular remodelling after myocardial infarction in mice

Division of Pathological Science, Department of Clinical Pharmacology, Kyoto Pharmaceutical University, 5 Misasagi Nakauchi-cho, Yamashina-ku, Kyoto 607-8414, Japan.
Cardiovascular Research (Impact Factor: 5.94). 03/2010; 87(3):424-30. DOI: 10.1093/cvr/cvq078
Source: PubMed

ABSTRACT The plasma level of interleukin-6 (IL-6) has been reported to be associated with left ventricular (LV) remodelling after myocardial infarction (MI). The present study was designed to examine whether anti-IL-6 receptor antibody (MR16-1) prevents the development of LV remodelling after MI.
Balb/c male mice were subjected to MI by ligating the left anterior descending coronary artery. The mice were then treated with an intraperitoneal injection of MR16-1 (500 microg/body) or control IgG. MR16-1 decreased the myocardial myeloperoxidase activity and monocyte chemoattractant protein-1 concentration in the infarct region, concomitant with decreases in neutrophil and macrophage infiltration 3 days after ligation, while infarct size was comparable between the control IgG- and MR16-1-treated mice. At 7 days after ligation, MR16-1 significantly suppressed matrix metalloproteinase-2 activity in the infarct region. Furthermore, the MR16-1-treated mice demonstrated a reduction in LV dilatation and an improvement in LV contractile function compared with the control IgG-treated mice at 7 and 28 days after surgery, leading to an improvement in survival rate (80.6 vs. 59.5%, P < 0.05) at 28 days after surgery. The beneficial effects of MR16-1 were accompanied by histological suppression of cardiomyocyte hypertrophy and interstitial fibrosis in the non-infarct region.
Administration of MR16-1 after MI suppressed myocardial inflammation, resulting in the amelioration of LV remodelling. Neutralization of the IL-6 receptor is a potentially useful strategy for protecting hearts from LV remodelling after MI.

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    • "affect the program of gene expression within the heart have been used in experimental models and/or clinical settings, including neutralizing antibodies (Purdham et al. 2008; Kobara et al. 2010), recombinant protein therapeutics (Hendel et al. 2000; Sato et al. 2001; Henry et al. 2003; Gao et al. 2011; Wu et al. 2011; Lin et al. 2012), microRNAs and antagomirs (van Rooij et al. 2008; Eulalio et al. 2012; Chen et al. 2013a; Hinkel et al. 2013), antisense oligonucleotides (Hagiwara et al. 2011), RNAi (Majmudar et al. 2013; Wu et al. 2014), and gene therapy via plasmid (Losordo et al. 1998; Stewart et al. 2009) and viral (Hedman et al. 2003; Stewart et al. 2006) vectors (Fig. 1). The development of new technology platforms to rapidly, transiently, and quantitatively express proteins exclusively in heart in vivo after injury in small and large animals, as well as in the clinically setting, could potentially enhance our capacity to quickly translate new findings in traditional genetic-based models systems toward clinical application. "
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    ABSTRACT: Over the past two decades, a host of new molecular pathways have been uncovered that guide mammalian heart development and disease. The ability to genetically manipulate these pathways in vivo have largely been dependent on the generation of genetically engineered mouse model systems or the transfer of exogenous genes in a variety of DNA vectors (plasmid, adenoviral, adeno-associated viruses, antisense oligonucleotides, etc.). Recently, a new approach to manipulate the gene program of the adult mammalian heart has been reported that will quickly allow the high-efficiency expression of virtually any protein in the intact heart of mouse, rat, porcine, nonhuman primate, and human heart cells via the generation of chemically modified mRNA (modRNA). The technology platform has important implications for delineating the specific paracrine cues that drive human cardiogenesis, and the pathways that might trigger heart regeneration via the rapid generation of modRNA libraries of paracrine factors for direct in vivo administration. In addition, the strategy can be extended to a variety of other cardiovascular tissues and solid organs across multiple species, and recent improvements in the core technology have supported moving toward the first human studies of modRNA in the next 2 years. These recent advances are reviewed along with projections of the potential impact of the technology for a host of other biomedical problems in the cardiovascular system.
    Cold Spring Harbor Perspectives in Medicine 10/2014; 5(1). DOI:10.1101/cshperspect.a014035 · 9.47 Impact Factor
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    • "Twenty-four hours after muscle ischemia, serum IL-6 levels were attenuated in the absence of MyD88 signaling. IL-6 has defined roles in muscle physiology and is released during strenuous exercise (Steensberg et al. 2002; Haddad et al. 2005; Serrano et al. 2008; McKay et al. 2009; Kobara et al. 2010). Its role in regulating muscle regeneration is multifactorial – in some systems, it is proregenerative while in others, the presence of IL-6 diminishes myoblast proliferation and differentiation (Steensberg et al. 2002; Haddad et al. 2005; Frost et al. 2006; McKay et al. 2009). "
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    ABSTRACT: We have previously shown that MyD88 KO mice appear protected from ischemic muscle injury while TRIF KO mice exhibit sustained necrosis after femoral artery ligation (FAL). However, our previous data did not differentiate whether the protective effect of absent MyD88 signaling was secondary to attenuated injury after FAL or quicker recovery from the insult. The purpose of this study was to delineate these different possibilities. On the basis of previous findings, we hypothesized that MyD88 signaling promotes enhanced inflammation while TRIF mediates regeneration after skeletal muscle ischemia. Our results show that after FAL, both MyD88 KO mice and TRIF KO mice have evidence of ischemia, as do their control counterparts. However, MyD88 KO mice had lower levels of serum IL-6 24 h after FAL, while TRIF KO mice demonstrated sustained serum IL-6 up to 1 week after injury. Additionally, MyD88 KO mice had higher nuclear content and larger myofibers than control animals 1 week after injury. IL-6 is known to have differential effects in myoblast function, and can inhibit proliferation and differentiation. In tibialis anterior muscle harvested from injured animals, IL-6 levels were higher and the proliferative marker MyoD was lower in TRIF KO mice by PCR. Furthermore, expression of MyD88 appeared to be higher in skeletal muscle of TRIF KO mice. In vitro, we showed that myoblast differentiation and proliferation were attenuated in response to IL-6 treatment giving credence to the finding that low IL-6 in MyD88 KO mice may be responsible for larger myocyte sizes 1 week after FAL. We conclude that MyD88 and TRIF work in concert to mediate a balanced response to ischemic injury.
    05/2014; 2(5). DOI:10.14814/phy2.12006
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    • "IL-6 infusions caused concentric left ventricular (LV) hypertrophy and significantly increased collagen deposition and ventricular stiffness [8]. Treatment with a monoclonal neutralizing antibody against IL-6 effectively ameliorated cardiac fibrosis associated with chronic rejection in rat cardiac allograft recipients [9], and in the non-infarct region in post-infarction mice [10]. Similarly, administration of anti-MCP-1 monoclonal neutralizing antibody potently attenuated pressure overload-induced cardiac fibrosis and ameliorated diastolic dysfunction in rats [4]. "
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    ABSTRACT: Background: Emerging evidence underlines the role of inflammation activation in the process of cardiac fibrosis. Triptolide has potent anti-inflammatory and anti-proliferative properties, and extensively used in the treatment of chronic inflammatory disorders. In the current study, we test the hypothesis that triptolide treatment facilitates to attenuate chronic pressure overload-induced cardiac fibrosis in a model of rat. Methods: Adult male Sprague-Dawley rats were subjected to a suprarenal abdominal aorta constriction (AC) or sham (as control) to induce sustained pressure overload. Eight weeks later, rats were randomly assigned to receive triptolide (9 μg/kg.d, i.p) or vehicle (0.1% dimethyl sulfoxide, 0.2 ml/d, i.p) treatment for an additional 8 weeks. Results: AC caused significant pathological hypertrophy, cardiac fibrosis and reduced cardiac diastolic function. Triptolide treatment markedly inhibited AC-induced increases in myocardial collagen volume fraction, collagen type I/III deposition, left ventricular end-diastolic pressure, expressions of pro-fibrogenic factors (transforming growth factor-β and angiotensin II) and pro-inflammatory cytokines (IL-1β and IL-6), NF-κB activation and inflammatory cell infiltration in left ventricles compared with vehicle, without affecting cardiac hypertrophy. However, triptolide had no effects on systemic blood pressure and circulating angiotensin II level. Conclusions: Collectively, the findings suggested that triptolide treatment elicits favorable anti-fibrogenic effect in a blood pressure-independent manner, at least in part, through inhibiting myocardial pro-fibrogenic factor production and inflammatory activation in the pressure overloaded heart.
    International journal of cardiology 03/2013; 168(3). DOI:10.1016/j.ijcard.2013.03.001 · 4.04 Impact Factor
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