Interleukin-18 knockout mice display maladaptive cardiac hypertrophy in response to pressure overload

Colston, James T.; Boylston, William H.; Feldman, Marc D.; Jenkinson, Chris; Rosa, Sam D. de la; Barton, Amanda K.; Trevino, Rodolfo J.; Freeman, Gregory L.; Chandrasekar, Bysani

doi:10.1016/j.bbrc.2007.01.030

Cited by 49 publications

(45 citation statements)

References 33 publications

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“…Similarly, a 20 younger age was associated with an increased transcription of inflammatory and immune modulatory cytokines. Several studies have confirmed the involvement of IL-1, IL-6, and IL-18 in myocardial inflammation, fibroblast proliferation, and increased collagen production (Colston et al, 2007;Chen et al, 2008;Yu et al, 2009;Hedayat et al, 2010;Tamariz and Hare, 2010;Fix et al, 2011). However, these cytokines are also involved in myocardial repair, compensatory ventricular hypertrophy and myocardial adjustment to changing haemodynamics (Colston et al, 2007;Yu et al, 2009;Hedayat et al, 2010;Fix et al, 2011).It is therefore possible that the observed inflammatory response is of benefit and enables myocardial repair (Chen and Frangogiannis, 2010;Chua et al, 2011).…”

Section: Discussionmentioning

confidence: 96%

Age- and gender-dependent myocardial transcription patterns of cytokines and extracellular matrix remodelling enzymes in cats with non-cardiac diseases

Fonfara

Hetzel

Hahn

et al. 2015

Experimental Gerontology

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Background:Age, genderand systemic diseases all influence cardiac function and remodelling.In cats, age and genderassociated myocardial remodelling and the effect of systemic diseases on the myocardium have so far not been studied. The aim of the study was therefore to investigate whetherrelevant cytokines and extracellular matrix (ECM) remodellingenzymesare expressed in the myocardium of cats with non-cardiac diseasesand whether transcription levels are influenced by age and gender. Methods:The study was performed on myocardial samples from 26 cats aged between 2 and 19 years that had died with non-cardiac diseases. Seventeen cats were female (2 entire), nine were male (1 entire). Of these, nine cats were diagnosed with diseases unlikely to affect the myocardium (control cats). The remaining 17 cats suffered from diseases with likely systemic effects.All hearts were assessed for any pathological changes, and the myocardium was analysed for interleukin (IL)-1, -2, -4, -6, -18, tumour necrosis factor (TNF)-, interferon(IFN)-, transforming growth factor (TGF)-, matrix metalloproteinase (MMP)-2, -3, -13, tissue inhibitor of MMP (TIMP)-1, -2 and -3 transcription using quantitative RT-PCR assays. Results:Despite the absence of any histological evidence of myocardial damage,inflammation and fibrosis, the myocardium of all cats was found to constitutively transcribe cytokines and ECM remodelling enzymes, with generally higher mRNA concentrations in atria than in ventricles.Young and male cats exhibited higher transcription levels throughout the myocardium in comparison to older and female cats. Furthermore, age-associated transcription pattern differed between male and female cats. Conclusion:The constitutive transcription of ECM remodellingenzymes suggests continuous myocardial remodelling throughout the entire life of a cat. The myocardium of young and malecats appears to be in a pro-inflammatory state, whereas in older and female cats the myocardium exhibits a reduced inflammatory reaction to systemic disease.Age-associated cardiac remodelling seems to be influenced bynon-hormonal factors inmale and female cats. Abstract: Background: Age, gender and systemic diseases all influence cardiac function and remodelling. In cats, age and gender associated myocardial remodelling and the effect of systemic diseases on the myocardium have so far not been studied. The aim of the study was therefore to investigate whether relevant cytokines and extracellular matrix (ECM) remodelling enzymes are expressed in the myocardium of cats with non-cardiac diseases and whether transcription levels are influenced by age and gender. Methods: The study was performed on myocardial samples from 26 cats aged between 2 and 19 years that had died with non-cardiac diseases. Seventeen cats were female (2 entire), nine were male (1 entire). Of these, nine cats were diagnosed with diseases unlikely to affect the myocardium (control cats). The remaining 17 cats suffered from diseases with likely systemic effects. All hearts were assessed fo...

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Section: Discussionmentioning

confidence: 96%

Age- and gender-dependent myocardial transcription patterns of cytokines and extracellular matrix remodelling enzymes in cats with non-cardiac diseases

Fonfara

Hetzel

Hahn

et al. 2015

Experimental Gerontology

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“…Moreover, IL-18 is significantly increased in the resident myocardial tissues and serum of heart failure patients (20,41). Several studies have emphasized the role of IL-18 in the pathophysiology of myocardial inflammation and injury (6,7,9). However, the fibrotic regulation of OPN by IL-18 in the stressed heart has not been elucidated.…”

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confidence: 99%

IL-18 induction of osteopontin mediates cardiac fibrosis and diastolic dysfunction in mice

Yu¹,

Vazquez²,

Khojeini³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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Osteopontin (OPN), a key component of the extracellular matrix, is associated with the fibrotic process during tissue remodeling. OPN and the cytokine interleukin (IL)-18 have been shown to be overexpressed in an array of human cardiac pathologies. In the present study, we determined the role of IL-18 in the regulation of cardiac OPN expression and the subsequent interstitial fibrosis and diastolic dysfunction. We demonstrated parallel increases in IL-18, OPN expression, and interstitial fibrosis in murine models of left ventricular pressure and volume overload. Exogenous recombinant (r)IL-18 administered for 2 wk increased cardiac OPN expression, interstitial fibrosis, and diastolic dysfunction. Stimulation of the T helper (Th)1 lymphocyte phenotype with a selective toll-like receptor (TLR)9 agonist induced cardiac IL-18 and OPN expression, which was associated with increased cardiac fibrillar collagen concentrations and interstitial fibrosis resulting in diastolic dysfunction. rIL-18 induced OPN expression and protein levels in primary of cardiac fibroblast cultures. Conditioned media from TLR9-stimulated T lymphocyte cultures induced IL-18 and OPN expression in cardiac fibroblasts, while blockade of the IL-18 receptor with a neutralizing antibody abolished the increase in OPN expression. Furthermore, a mutation in the transcriptional factor interferon regulatory factor (IRF)1 or IRF1 small interfering RNA (siRNA) resulted in the decreased expression of IL-18 and OPN in cardiac fibroblasts. With pressure overload, IRF1-mutant mice showed downregulation of IL-18 and OPN expression in cardiac tissue, reduced cardiac fibrotic development, and increased left ventricular function compared with wild type. These results provide direct evidence that the induction of IL-18 regulates OPN-mediated cardiac fibrosis and diastolic dysfunction. extracellular matrix; remodeling; T lymphocyte; interferon regulatory factor 1; toll-like receptor-9; lysyl oxidase LEFT VENTRICULAR REMODELING in response to pressure and/or volume overload is associated with myocardial hypertrophy, fibroblast hyperplasia, and increased concentrations of fibrillar collagen in the extracellular matrix. Recent studies have shown that pathological myocardial fibrosis may cause diastolic dysfunction and heart failure (24), whereas myocyte hypertrophy in the absence of fibrosis is considered physiological remodeling (22, 46) if the mass-to-volume ratio is preserved (5). In this study, we investigated whether interleukin (IL)-18 regulates the gene and protein expression of the matricellular protein osteopontin (OPN), a component and regulator of cardiac extracellular matrix fibrillar collagen concentrations.As reviewed by Okamoto (26), OPN also plays a critical role in the regulation of cellular proliferation and differentiation, interstitial fibrosis, arteriosclerosis, and angiogenesis. Although OPN is ubiquitously expressed in many tissues and is increased during stress-induced cardiac remodeling, it participates as a cytokine or humoral factor in the in...

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“…Considering the role of IL-18 in mediating acute cardiac effects such as contractile dysfunction and β-AR desensitization as well as chronic cardiac changes like hypertrophy and fibrosis, it is reasonable to hypothesize that IL-18 blockade may represent a valuable strategy in both acute and chronic cardiac diseases (Figure 4). Genetic deletion or neutralization of IL-18 reduces myocyte hypertrophy in models of pressure overload or LPS-induced myocardial dysfunction (60,72). Preventing IL-18 activity by pretreatment with a neutralizing antibody, IL-18BPa, NLRP3 inhibitors or caspase-1 inhibitors improves contractile function and decreases infarct size after ischemia-reperfusion injury, providing the basis for additional studies of these molecules in AMI (63,71,90).…”

Section: Discussionmentioning

confidence: 99%

“…Inflammatory cytokines contribute to the pathophysiology of HFPEF (96,99), thus IL-18 is a potential target for HFPEF due to its prohypertrophic and profibrotic effects (56)(57)(58)(59)(60)84,86,87). The chronic prohypertrophic and profibrotic effects of IL-18 in animal studies suggest that a longer duration of IL-18 blockade may prevent, or even reverse, the development of pathologic cardiac hypertrophy; however it also may prevent development of physiologic hypertrophy (53).…”

Section: Discussionmentioning

confidence: 99%

“…Daily administration of IL-18 to healthy mice induces ANP expression in the heart, myocardial hypertrophy, and contractile dysfunction (58,59). IL-18 knockout (KO) mice subjected to pressure overload developed less hypertrophy, which is a key feature of the pathology, but also had worse contractile function (60). IL-18 KO mice, as well as mice treated with an IL-18 blocking antibody or with rh-IL-18BP showed a significantly blunted hypertrophic response to isoproterenol (IPO); the effects on cardiac function were not reported (61).…”

Section: Cardiomyocyte Hypertrophymentioning

confidence: 99%

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Interleukin-18 as a Therapeutic Target in Acute Myocardial Infarction and Heart Failure

O’Brien

Mezzaroma

Tassell

et al. 2014

Mol Med

112

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Interleukin 18 (IL-18) is a proinflammatory cytokine in the IL-1 family that has been implicated in a number of disease states. In animal models of acute myocardial infarction (AMI), pressure overload, and LPS-induced dysfunction, IL-18 regulates cardiomyocyte hypertrophy and induces cardiac contractile dysfunction and extracellular matrix remodeling. In patients, high IL-18 levels correlate with increased risk of developing cardiovascular disease (CVD) and with a worse prognosis in patients with established CVD. Two strategies have been used to counter the effects of IL-18:IL-18 binding protein (IL-18BP), a naturally occurring protein, and a neutralizing IL-18 antibody. Recombinant human IL-18BP (r-hIL-18BP) has been investigated in animal studies and in phase I/II clinical trials for psoriasis and rheumatoid arthritis. A phase II clinical trial using a humanized monoclonal IL-18 antibody for type 2 diabetes is ongoing. Here we review the literature regarding the role of IL-18 in AMI and heart failure and the evidence and challenges of using IL-18BP and blocking IL-18 antibodies as a therapeutic strategy in patients with heart disease.

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Interleukin-18 knockout mice display maladaptive cardiac hypertrophy in response to pressure overload

Cited by 49 publications

References 33 publications

Age- and gender-dependent myocardial transcription patterns of cytokines and extracellular matrix remodelling enzymes in cats with non-cardiac diseases

Age- and gender-dependent myocardial transcription patterns of cytokines and extracellular matrix remodelling enzymes in cats with non-cardiac diseases

IL-18 induction of osteopontin mediates cardiac fibrosis and diastolic dysfunction in mice

Interleukin-18 as a Therapeutic Target in Acute Myocardial Infarction and Heart Failure

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