Tumor necrosis factor-alpha antagonism protects from myocardial inflammation and fibrosis in experimental diabetic cardiomyopathy

Westermann, Dirk; Linthout, Sophie Van; Dhayat, Sameer; Dhayat, Nasser; Schmidt, Anja; Noutsias, Michel; Song, X.-Y.; Spillmann, Frank; Riad, Alexander; Schultheiss, Heinz‐Peter; Tschöpe, Carsten

doi:10.1007/s00395-007-0673-0

Cited by 187 publications

(135 citation statements)

References 43 publications

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“…Consistent with our findings in these mice, nontransgenic models of lipid overload using long-term high-fat diet or streptozotocin treatment have also demonstrated increased numbers of macrophages within the hearts of insulin resistant and/or diabetic mice (13,30). However, assessing the influence of cardiac macrophages on LV function using cell depletion strategies with these models is confounded by the concomitant role of macrophages in promoting the primary dysregulation of systemic metabolism, which is further modified by macrophage depletion (16,21).…”

Section: Discussionsupporting

confidence: 77%

Macrophages modulate cardiac function in lipotoxic cardiomyopathy

Schilling

Machkovech

Kim

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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Schilling JD, Machkovech HM, Kim AH, Schwedwener R, Schaffer JE. Macrophages modulate cardiac function in lipotoxic cardiomyopathy. Am J Physiol Heart Circ Physiol 303: H1366 -H1373, 2012. First published October 5, 2012; doi:10.1152/ajpheart.00111.2012.-Diabetes is associated with myocardial lipid accumulation and an increased risk of heart failure. Although cardiac myocyte lipid overload is thought to contribute to the pathogenesis of cardiomyopathy in the setting of diabetes, the mechanism(s) through which this occurs is not well understood. Increasingly, inflammation has been recognized as a key pathogenic feature of lipid excess and diabetes. In this study, we sought to investigate the role of inflammatory activation in the pathogenesis of lipotoxic cardiomyopathy using the ␣-myosin heavy chain promoter-driven long-chain acylCoA synthetase 1 (MHC-ACS) transgenic mouse model. We found that several inflammatory cytokines were upregulated in the myocardium of MHC-ACS mice before the onset of cardiac dysfunction, and this was accompanied by macrophage infiltration. Depletion of macrophages with liposomal clodrolip reduced the cardiac inflammatory response and improved cardiac function. Thus, in this model of lipotoxic cardiac injury, early induction of inflammation and macrophage recruitment contribute to adverse cardiac remodeling. These findings have implications for our understanding of heart failure in the setting of obesity and diabetes. heart failure; diabetes; inflammation OBESITY AND DIABETES ARE SIGNIFICANT risk factors for the development of heart failure (11). In many diabetic patients, this can occur in the absence of underlying coronary artery disease or hypertension, a phenomenon known as diabetic cardiomyopathy (1). The pathogenesis of diabetic cardiomyopathy is complex; however, myocardial lipid overload is a pathologic feature of this condition in humans and in animal models (6,7,12,25). The observation that cardiac myocyte lipid overload causes cardiomyopathy in genetic mouse models, without systemic abnormalities of insulin or glucose metabolism, supports the notion that excess lipids can be cardiotoxic (4,5,7,32). Membrane lipid remodeling, endoplasmic reticulum and oxidative stress, and production of toxic lipid species, such as ceramides, have been implicated as potential mechanisms of cardiac lipotoxicity (12,23).Systemic inflammation is another hallmark of obesity and diabetes and has been shown to correlate with the risk of heart failure in patients with these metabolic conditions (2). This raises the intriguing possibility that lipid-induced inflammatory responses might contribute to cardiac dysfunction in obesity and diabetes. Much of what is known regarding the link between diabetes and inflammation has come from investigations of adipose tissue. In humans and animals, obesity triggers the recruitment of macrophages to white adipose tissue, which is followed by release of inflammatory mediators and the onset of insulin resistance (26,29). When this response is interrupted in mice fed...

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Section: Discussionsupporting

confidence: 77%

Macrophages modulate cardiac function in lipotoxic cardiomyopathy

Schilling

Machkovech

Kim

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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“…5A) supported the conclusion that JNK mediated HGinduced caspase-3 activation and intrinsic apoptotic pathways. TNF-a, which is increased by HG induction, also induces cardiac apoptosis through its type 1 receptor complex II, a classic death receptor (18). The binding between TNF-a and TNF-a type 1 receptor complex II results in the activation of the JNK-dependent caspase cascade and then commits cells to apoptosis (40).…”

Section: Discussionmentioning

confidence: 99%

“…Two groups have shown that TNF provokes cardiomyocyte apoptosis and cardiac remodeling through the activation of multiple cell-death pathways under diabetic conditions and in the pressure overload state, respectively (16,17). Intervention against TNF-a using a specific antagonist was reported to protect against cardiac inflammation, apoptosis, and fibrosis in experimental diabetic cardiomyopathy (18). This suggests that inhibition of inflammatory cytokines may be an effective strategy for the prevention of diabetes-induced pathogenic changes in the heart.…”

mentioning

confidence: 99%

Inhibition of JNK Phosphorylation by a Novel Curcumin Analog Prevents High Glucose–Induced Inflammation and Apoptosis in Cardiomyocytes and the Development of Diabetic Cardiomyopathy

Pan¹,

et al. 2014

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Hyperglycemia-induced inflammation and apoptosis have important roles in the pathogenesis of diabetic cardiomyopathy. We recently found that a novel curcumin derivative, C66, is able to reduce the high glucose (HG)-induced inflammatory response. This study was designed to investigate the protective effects on diabetic cardiomyopathy and its underlying mechanisms. Pretreatment with C66 significantly reduced HG-induced overexpression of inflammatory cytokines via inactivation of nuclear factor-κB in both H9c2 cells and neonatal cardiomyocytes. Furthermore, we showed that the inhibition of Jun NH2-terminal kinase (JNK) phosphorylation contributed to the protection of C66 from inflammation and cell apoptosis, which was validated by the use of SP600125 and dominant-negative JNK. The molecular docking and kinase activity assay confirmed direct binding of C66 to and inhibition of JNK. In mice with type 1 diabetes, the administration of C66 or SP600125 at 5 mg/kg significantly decreased the levels of plasma and cardiac tumor necrosis factor-α, accompanied by decreasing cardiac apoptosis, and, finally, improved histological abnormalities, fibrosis, and cardiac dysfunction without affecting hyperglycemia. Thus, this work demonstrated the therapeutic potential of the JNK-targeting compound C66 for the treatment of diabetic cardiomyopathy. Importantly, we indicated a critical role of JNK in diabetic heart injury, and suggested that JNK inhibition may be a feasible strategy for treating diabetic cardiomyopathy.

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“…Additionally, we have documented that increased plasma N-terminal brain natriuretic peptide levels in patients with chronic rheumatic valve disease is a potential marker of disease severity and correlates with symptoms (Davutoglu et al 2005b). However, it is well documented that cytokines like TNF-alpha increase intramyocardial inflammation and cardiac fibrosis and thus may lead to cardiomyopathy (Westermann et al 2007). Furthermore, attenuation of development of experimental cardiomyopathy by the antagonism of such cytokines has been documented (Suzuki et al 2007).…”

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confidence: 99%