Increased Myocardial Tumor Necrosis Factor-α in a Crystalloid-Perfused Model of Cardiac Ischemia-Reperfusion Injury

Meldrum, Daniel R.; Cleveland, Joseph C.; Cain, Brian S.; Meng, Xianzhong; Harken, Alden H.

doi:10.1016/s0003-4975(97)01297-6

Cited by 110 publications

(64 citation statements)

References 27 publications

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“…18 TNF-a is a proimflammatory cytokine that has been implicated in the pathogenesis of cardiovascular diseases such as acute myocardial infarction, chronic heart failure and atherosclerosis, and cardiac overexpression of TNF-a causes LV remodeling. 30 IL-6 is secreted by cardiomyocyte and increased in failing hearts. 31 The increased IL-6 is involved in diabetic deterioration and may be associated with cardiac hypertrophy.…”

Section: Discussionmentioning

confidence: 99%

Cardiac remodeling and diastolic dysfunction in DahlS.Z-Leprfa/Leprfa rats: a new animal model of metabolic syndrome

et al. 2011

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We recently characterized male DahlS.Z-Lepr fa /Lepr fa (Dahl salt-sensitive (DS)/obese) rats, which were established from a cross between Dahl salt-sensitive and Zucker rats, as a new animal model of metabolic syndrome (MetS). We have now investigated cardiac pathophysiology and metabolic changes in female DS/obese rats in comparison with homozygous lean female littermates (DahlS.Z-Lepr + /Lepr + , or DS/lean, rats). Animals were maintained on a normal diet and were subjected to echocardiography followed by various pathological analyses at 15 weeks of age. Systolic blood pressure was significantly higher in female DS/obese rats than in DS/lean females at 12 weeks of age and thereafter. The survival rate of DS/obese rats was significantly lower than that of DS/lean rats at 15 weeks. Body weight, as well as visceral and subcutaneous fat mass were significantly increased in DS/obese rats, which also manifested left ventricular (LV) diastolic dysfunction and marked LV hypertrophy and fibrosis. In addition, myocardial oxidative stress and inflammation were increased in DS/obese rats compared with DS/lean rats. Serum insulin and triglyceride levels as well as the ratio of low-density lipoprotein-to high-density lipoprotein-cholesterol levels were markedly elevated in DS/obese rats, whereas fasting serum glucose concentrations were similar in the two rat strains. The phenotype of female DS/obese rats is similar to that of MetS in humans. These animals also develop salt-sensitive hypertension and LV diastolic dysfunction as well as LV hypertrophy and fibrosis, and these changes are associated with increased cardiac oxidative stress and inflammation. Keywords: cardiac hypertrophy; diastolic dysfunction; metabolic syndrome; myocardial fibrosis; salt-sensitive hypertension INTRODUCTION Metabolic syndrome (MetS), a complex of highly debilitating disorders including hypertension, diabetes mellitus and dyslipidemia, is associated with the development of visceral obesity. 1 Adipocytes in visceral fat of obese humans secrete a variety of biological agents that are known as adipocytokines and include proinflammatory cytokines such as tumor necrosis factor (TNF)-a and interleukin (IL)-6 as well as angiotensinogen and leptin. 2 Recent studies have revealed intricate interactions among adipocytes, the sympathetic nervous system and the renin-angiotensin-aldosterone system (RAAS) that contribute to the disturbed metabolic state associated with obesity. 3 Indeed, adipose tissue is thought to have an important role in the development of both hypertension and other complications related to insulin resistance. Activation of the RAAS and associated oxidative stress can result in mitochondrial abnormalities, altered bioenergetics and the accumulation of lipids in the heart, and thereby increase susceptibility to metabolic cardiomyopathy. 4

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Section: Discussionmentioning

confidence: 99%

Cardiac remodeling and diastolic dysfunction in DahlS.Z-Leprfa/Leprfa rats: a new animal model of metabolic syndrome

et al. 2011

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“…Global warm ischemia and reperfusion of isolated rat hearts rapidly increases TNF-␣ in the coronary effluent and in the myocardium. 24,25 When the left anterior descending coronary artery is temporarily occluded, TNF-␣ and IL-1␤ gene expression peaks at 60 minutes after resumption of the blood supply, a time course similar to their early activation in brain-dead donor hearts after transplantation. 10,11 The effect of I/R on MCP-1 production in rat and dog cardiac ischemia models is also comparable to that seen in the present studies.…”

Section: Wilhelm Et Al Donor Brain Death Influences Heart Graft Survimentioning

confidence: 99%

Activation of the Heart by Donor Brain Death Accelerates Acute Rejection After Transplantation

et al. 2000

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Background-Donor brain death upregulates expression of inflammatory mediators in the heart. It is hypothesized that these nonspecific changes trigger and amplify acute rejection in unmodified recipients compared with hearts from normal living donors. We examined the inflammatory and immunological consequences of gradual-onset donor brain death on cardiac allografts after transplantation. Methods and Results-Functioning hearts were engrafted from normotensive donors after 6 hours of ventilatory support.Hearts from brain-dead rats (Fisher, F344) were rejected significantly earlier (meanϮSD, 9.3Ϯ0.6 days) by their (Lewis) recipients than hearts from living donor controls (11.6Ϯ0.7 days, Pϭ0.03). The inflammatory response of such organs was accelerated, with rapid expression of cytokines, chemokines, and adhesion molecules and brisk infiltration of associated leukocyte populations. Upregulation of major histocompatibility class II antigens increased organ immunogenicity. Acute rejection evolved in hearts from brain-dead donors more intensely and at a significantly faster rate than in controls. Conclusions-Donor brain death is deleterious to transplanted hearts. The resultant upregulation of inflammatory factors provokes host immune mechanisms and accelerates the acute rejection process in unmodified hosts. (Circulation.

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“…Several studies have shown that chemotherapy-induced cardiotoxicity (CTX) produced by ANTs is at least partially mediated by chronic inflammation and oxidative stress, with proinflammatory cytokines, interleukin-6 (IL-6) and tumor necrosis factor (TNF)-α and reactive oxygen species (ROS) (2) playing a central role (5,6). It has also been shown that the use of a conventional cardioprotective agent, such as dexrazoxane, together with chemotherapy, reduces the expression of the NRF-2 gene (responsible for oxidative stress response), which is overexpressed in patients receiving ANT alone (2).…”

Section: Introductionmentioning

confidence: 99%

Long-term protective effects of the angiotensin receptor blocker telmisartan on epirubicin-induced inflammation, oxidative stress and myocardial dysfunction

Dessì

Piras

Madeddu

et al. 2011

Experimental and Therapeutic Medicine

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Abstract. Chronic inflammation, oxidative stress and the renin-angiotensin system (RAS) play a significant role in chemotherapy-induced cardiotoxicity (CTX). Telmisartan (TEL), an antagonist of the angiotensin II type-1 receptor, was found to reduce anthracycline (ANT)-induced CTX. We carried out a phase II placebo (PLA)-controlled randomized trial to assess the possible role of TEL in the prevention of cardiac subclinical damage induced by epirubicin (EPI). Forty-nine patients (mean age ± SD, 53.0±8 years), cardiovascular diseasefree with cancer at different sites and eligible for EPI-based treatment, were randomized to one of two arms: TEL n=25; PLA n=24. A conventional echocardiography equipped with Tissue Doppler imaging, strain and strain rate (SR) was performed, and serum levels of proinflammatory cytokines, IL-6 and TNF-α, and oxidative stress parameters, reactive oxygen species (ROS) and glutathione peroxidase were determined. All assessments were carried out at baseline, after every 100 mg/m 2 of EPI dose and at the 12-month follow-up (FU). A significant reduction in the SR peak both in the TEL and PLA arms was observed at t 2 (cumulative dose of 200 mg/m 2 of EPI) in comparison to t 0 . Conversely, at t 3 (300 mg/m 2 EPI), t 4 (400 mg/m 2 EPI) and the 12-month FU, the SR increased reaching the normal range only in the TEL arm, while in the PLA arm the SR remained significantly lower as compared to t 0 (baseline). The differences between SR changes in the PLA and TEL arms were significant from 300 mg/m 2 EPI (t 3 ) up to the 12-month FU. Serum levels of IL-6 increased significantly in the PLA arm at 200 mg/m 2 EPI (t 2 ) in comparison to baseline, but remained unchanged in the TEL arm. The same trend was demonstrated for ROS levels which significantly increased at t 2 vs. baseline in the PLA arm, while remained unchanged in the TEL arm. The mean change in ROS and IL-6 at t 2 was significantly different between the two arms. In the present study, we confirmed at the 3-month FU a trend toward a decrease in ROS and IL-6 from t 2 in the PLA arm. Our results suggest that TEL is able to reverse acute (early) EPI-induced myocardial dysfunction and to maintain later a normal systolic function up to the 12-month FU. These effects are likely to be due to different mechanisms, RAS blockade and prevention of chronic inflammation/oxidative stress. IntroductionAnthracyclines (ANTs) are among the most effective anticancer drugs used in the treatment of a wide spectrum of malignancies. Regrettably, their clinical use is limited by the occurrence of dose-related cardiotoxicity (4).Several studies have shown that chemotherapy-induced cardiotoxicity (CTX) produced by ANTs is at least partially mediated by chronic inflammation and oxidative stress, with proinflammatory cytokines, interleukin-6 (IL-6) and tumor necrosis factor (TNF)-α and reactive oxygen species (ROS) (2) playing a central role (5,6). It has also been shown that the use of a conventional cardioprotective agent, such as dexrazoxane,

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Increased Myocardial Tumor Necrosis Factor-α in a Crystalloid-Perfused Model of Cardiac Ischemia-Reperfusion Injury

Cited by 110 publications

References 27 publications

Cardiac remodeling and diastolic dysfunction in DahlS.Z-Leprfa/Leprfa rats: a new animal model of metabolic syndrome

Cardiac remodeling and diastolic dysfunction in DahlS.Z-Leprfa/Leprfa rats: a new animal model of metabolic syndrome

Activation of the Heart by Donor Brain Death Accelerates Acute Rejection After Transplantation

Long-term protective effects of the angiotensin receptor blocker telmisartan on epirubicin-induced inflammation, oxidative stress and myocardial dysfunction

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