Serum but not myocardial TNF-α concentration is increased in  pacing-induced heart failure in rabbits

Aker, Stephanie; Belosjorow, Sergej; Konietzka, Ina; Duschin, Alexej; Martin, Claus; Heusch, Gerd; Schulz, Rainer

doi:10.1152/ajpregu.00153.2003

Cited by 37 publications

(31 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, work from Becker's laboratory (16,29) indicates that TNF-␣ derived from mast cells is the initial source of increased release following ischemia reperfusion. However, multiple cell types and organs may contribute to the increases in serum TNF-␣ characteristic of heart failure, including cardiomyocytes and the liver (1,14,23).…”

Section: Discussionmentioning

confidence: 99%

TNF-α inhibition attenuates adverse myocardial remodeling in a rat model of volume overload

Jobe

Meléndez

Levick

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

Jobe LJ, Meléndez GC, Levick SP, Du Y, Brower GL, Janicki JS. TNF-␣ inhibition attenuates adverse myocardial remodeling in a rat model of volume overload. Am J Physiol Heart Circ Physiol 297: H1462-H1468, 2009. First published August 7, 2009 doi:10.1152/ajpheart.00442.2009.-Tumor necrosis factor (TNF)-␣ is a proinflammatory cytokine that has been implicated in the pathogenesis of heart failure. In contrast, we have recently shown that myocardial levels of TNF-␣ are acutely elevated in the aortocaval (AV) fistula model of heart failure. Based on these observations, we hypothesized that progression of adverse myocardial remodeling secondary to volume overload would be prevented by inhibition of TNF-␣ with etanercept. Furthermore, a principal objective of this study was to elucidate the effect of TNF-␣ inhibition during different phases of the myocardial remodeling process. Eight-week-old male Sprague-Dawley rats were randomly divided into the following three groups: sham-operated controls, untreated AV fistulas, and etanercept-treated AV fistulas. Each group was further subdivided to study three different time points consisting of 3 days, 3 wk, and 8 wk postfistula. Etanercept was administered subcutaneously at 1 mg/kg body wt. Etanercept prevented collagen degradation at 3 days and significantly attenuated the decrease in collagen at 8 wk postfistula. Although TNF-␣ antagonism did not prevent the initial ventricular dilatation at 3 wk postfistula, etanercept was effective at significantly attenuating the subsequent ventricular hypertrophy, dilatation, and increased compliance at 8 wk postfistula. These positive adaptations achieved with etanercept administration translated into significant functional improvements. At a cellular level, etanercept also markedly attenuated increases in cardiomyocyte length, width, and area at 8 wk postfistula. These observations demonstrate that TNF-␣ has a pivotal role in adverse myocardial remodeling and that treatment with etanercept can attenuate the progression to heart failure. diastolic function; intrinsic contractility; myocyte dimensions; etanercept; extracellular matrix; ventricular pressure-volume relationship THE PROINFLAMMATORY CYTOKINE tumor necrosis factor-␣ (TNF-␣) has been documented to elicit a variety of responses in the heart ranging from cardioprotective to pathological (3,4,14,23,(32)(33)(34). However, chronically elevated levels of TNF-␣ have been identified as a risk factor for coronary heart disease and congestive heart failure (12,22,23). Consistent with this, Bozkurt et al. (3) demonstrated that a chronic infusion of rats with pathological levels of TNF-␣ was sufficient to induce myocardial remodeling consisting of left ventricular (LV) wall thinning, dilatation, and collagen degradation, resulting in reduced myocardial function. Furthermore, collagen degradation due to increased matrix metalloproteinase (MMP) activity and a reduction in tissue inhibitor of metalloproteinases-1 (TIMP-1) in mice with cardiac-restricted overexpression of TNF-␣ has been imp...

show abstract

Section: Discussionmentioning

confidence: 99%

TNF-α inhibition attenuates adverse myocardial remodeling in a rat model of volume overload

Jobe

Meléndez

Levick

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

show abstract

“…The main data leading to these conclusions are as follows: (1) TNF-␣-induced preconditioning did not phosphorylate the kinases Akt and Erk during reperfusion; (2) specific inhibitors of these kinases did not affect cardioprotection by TNF-␣; (3) TNF-␣ and classic IPC phosphorylated STAT-3 during early reperfusion; and (4) addition of the STAT-3 inhibitor AG 490 abolished the protection afforded by both TNF-␣ and IPC as preconditioning stimuli. During ischemia, 25 in heart failure, 26 or after coronary microembolization, 27 myocardial and/or serum TNF-␣ levels increase and are causally involved in contractile dysfunction. In contrast, in vitro experiments conducted in rats or in mouse hearts have shown that exogenous TNF-␣ could also confer cardioprotection against an I/R insult in a time-and dosedependent manner.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Preconditioning With Tumor Necrosis Factor-α Activates Signal Transducer and Activator of Transcription-3 at Reperfusion Without Involving Classic Prosurvival Kinases (Akt and Extracellular Signal–Regulated Kinase)

et al. 2005

View full text Add to dashboard Cite

Background-We previously reported that tumor necrosis-factor-␣ (TNF-␣) can mimic classic ischemic preconditioning (IPC) in a dose-and time-dependent manner. Because TNF-␣ activates the signal transducer and activator of transcription-3 (STAT-3), we hypothesized that TNF-␣-induced preconditioning requires phosphorylation of STAT-3 rather than involving the classic prosurvival kinases, Akt and extracellular signal-regulated kinase (Erk) 1/2, during early reperfusion. Methods and Results-Isolated, ischemic/reperfused rat hearts were preconditioned by either IPC or low-dose TNF-␣ (0.5 ng/mL). Western blot analysis confirmed that IPC phosphorylated Akt and Erk 1/2 after 5 minutes of reperfusion (Akt increased by 34Ϯ6% and Erk, by 105Ϯ28% versus control; PϽ0.01). Phosphatidylinositol 3-kinase/Akt inhibition (wortmannin) or mitogen-activated protein kinase-Erk 1/2 kinase inhibition (PD-98059) during early reperfusion abolished the infarct-sparing effect of IPC. In contrast, TNF-␣ preconditioning did not phosphorylate these kinases (Akt increased by 7Ϯ7% and Erk, by 17Ϯ14% versus control; PϭNS). Neither wortmannin nor PD-98059 inhibited TNF-␣-mediated cardioprotection. However, TNF-␣ and IPC both phosphorylated STAT-3 and the proapoptotic protein Bcl-2 antagonist of cell death (BAD) (STAT-3 increased by 58Ϯ17% with TNF-␣ or by 68Ϯ12% with IPC; BAD increased by 75Ϯ8% with TNF-␣ or by 205Ϯ20% with IPC; PϽ0.01 versus control), thereby activating the former and inactivating the latter. The STAT-3 inhibitor AG 490 abolished cardioprotection and BAD phosphorylation with both preconditioning stimuli. Conclusions-Activation of the classic prosurvival kinases (Akt and Erk 1/2) is not essential for TNF-␣-induced preconditioning in the early reperfusion phase. We show the existence of an alternative protective pathway that involves STAT-3 activation specifically at reperfusion in response to both TNF-␣ and classic IPC. This novel prosurvival pathway may have potential therapeutic significance. (Circulation. 2005;112:3911-3918.)

show abstract

“…Serum was obtained by centrifuging the blood at 8,000 g for 15 min at 4°C. Liver samples and intestinal contents were prepared as described elsewhere (1). Briefly, liver tissues and intestinal contents from ileum, cecum, and colon lumen were weighed, collected in sterile, endotoxin-free tubes, diluted with limulus LAL reagent water (1:10 for liver tissues, 1:1,000 for intestinal contents samples), and homogenized.…”

Section: Animals and Treatmentsmentioning

confidence: 99%

Dietary fat sources differentially modulate intestinal barrier and hepatic inflammation in alcohol-induced liver injury in rats

Zhong

Xie

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

View full text Add to dashboard Cite

toxemia is a causal factor in the development of alcoholic liver injury. The present study aimed at determining the interactions of ethanol with different fat sources at the gut-liver axis. Male Sprague-Dawley rats were pair fed control or ethanol liquid diet for 8 wk. The liquid diets were based on a modified Lieber-DeCarli formula, with 30% total calories derived from corn oil (rich in polyunsaturated fatty acids). To test the effects of saturated fats, corn oil in the ethanol diet was replaced by either cocoa butter (CB, rich in long-chain saturated fatty acids) or medium-chain triglycerides (MCT, exclusively medium-chain saturated fatty acids). Ethanol feeding increased hepatic lipid accumulation and inflammatory cell infiltration and perturbed hepatic and serum metabolite profiles. Ethanol feeding with CB or MCT alleviated ethanol-induced liver injury and attenuated ethanolinduced metabolic perturbation. Both CB and MCT also normalized ethanol-induced hepatic macrophage activation, cytokine expression, and neutrophil infiltration. Ethanol feeding elevated serum endotoxin level, which was normalized by MCT but not CB. In accordance, ethanol-induced downregulations of intestinal occludin and zonula occludens-1 were normalized by MCT but not CB. However, CB normalized ethanol-increased hepatic endotoxin level in association with upregulation of an endotoxin detoxifying enzyme, argininosuccinate synthase 1 (ASS1). Knockdown ASS1 in H4IIEC3 cells resulted in impaired endotoxin clearance and upregulated cytokine expression. These data demonstrate that the protection of saturated fats against alcohol-induced liver injury occur via different actions at the gut-liver axis and are chain length dependent. alcohol; saturated fat; endotoxemia; inflammation; liver injury ALCOHOLIC LIVER DISEASE (ALD) is a major health problem worldwide (19,41). Endotoxemia is closely associated with the pathogenesis of ALD through the stimulation of proinflammatory cytokine production (6, 37). Significantly increased levels of endotoxin were found in both alcoholic patients and experimental animal models of ALD, and the levels correlated well with the development of liver injury (7). Our previous study showed that neutralization of endotoxin by endotoxin neutralizing protein attenuates acute alcohol-induced cytokine production and liver injury, suggesting the importance of endotoxins in mediating alcoholic hepatotoxicity (51). Mechanistic studies have suggested that intestinal bacterial overgrowth and intestinal permeability increase contribute to the development of endotoxemia in alcoholics (35, 37). Our previous work showed that orally administrated lipopolysaccharide was detectable in the plasma of alcohol-intoxicated mice but not in control mice (52), providing direct evidence that alcohol increases gut permeability to endotoxins. Animal studies also showed that prevention of gut leakiness resulted in suppression of alcohol exposure-induced endotoxemia and liver damage (18, 44), suggesting that gut leakiness is a causal factor in the...

show abstract

Serum but not myocardial TNF-α concentration is increased in pacing-induced heart failure in rabbits

Cited by 37 publications

References 48 publications

TNF-α inhibition attenuates adverse myocardial remodeling in a rat model of volume overload

TNF-α inhibition attenuates adverse myocardial remodeling in a rat model of volume overload

Pharmacological Preconditioning With Tumor Necrosis Factor-α Activates Signal Transducer and Activator of Transcription-3 at Reperfusion Without Involving Classic Prosurvival Kinases (Akt and Extracellular Signal–Regulated Kinase)

Dietary fat sources differentially modulate intestinal barrier and hepatic inflammation in alcohol-induced liver injury in rats

Contact Info

Product

Resources

About