Myocardial Tumor Necrosis Factor Research Articles

Breviscapine alleviates myocardial ischemia-reperfusion injury in diabetes rats.

To investigate the protective effect of breviscapine on myocardial ischemia-reperfusion injury (MIRI) in diabetes rats. Forty rats were divided into control, diabetes, MIRI of diabetes, and treatment groups. The MIRI of diabetes model was established in the latter two groups. Then, the treatment group was treated with 100 mg/kg breviscapine by intraperitoneal injection for 14 consecutive days. After treatment, compared with MIRI of diabetes group, in treatment group the serum fasting blood glucose, fasting insulin, homeostasis model assessment of insulin resistance, and glycosylated hemoglobin levels decreased, the serum total cholesterol, triacylglycerol, and low-density lipoprotein cholesterol levels decreased, the serum high-density lipoprotein cholesterol level increased, the heart rate decreased, the mean arterial pressure, left ventricular ejection fraction, and fractional shortening increased, the serum cardiac troponin I, and creatine kinase-MB levels decreased, the myocardial tumor necrosis factor α and interleukin-6 levels decreased, the myocardial superoxide dismutase level increased, and the myocardial malondialdehyde level decreased (all P < 0.05). For treating MIRI of diabetes in rats, the breviscapine can reduce the blood glucose and lipid levels, improve the cardiac function, reduce the myocardial injury, and decrease the inflammatory response and oxidative stress, thus exerting the alleviating effect.

Effects of isoflurane preconditioning in the delayed phase on myocardial tumor necrosis factor alpha levels and caspase-3 protein expression in a rabbit model of ischemia-reperfusion injury.

This study aimed to investigate the protective effects and the mechanisms underlying these effects of isoflurane preconditioning in the delayed phase of myocardial ischemia-reperfusion injury. We randomly divided 30 healthy male New Zealand white rabbits into three groups with 10 rabbits in each group as follows: sham operation group (C group), ischemia-reperfusion group (I/R group), and 2.0% isoflurane preconditioning group (S group). Rabbits in the C group received thoracotomy for 160 min. Rabbits in the I/R group underwent left coronary artery occlusion for 40 min and reperfusion for 120 min. Rabbits in the S group received inhalation of 2.0% isoflurane and 100% oxygen for 2 h; after 24 h, rabbits in this group received the same treatment as that administered to rabbits in the I/R group. We examined the tumor necrosis factor alpha (TNF-α) levels in each group 20 min before occlusion of the left coronary, 20 and 40 min after occlusion of the left coronary artery, and 1 and 2 h after myocardial reperfusion. After reperfusion, immunoblotting was used to measure the myocardial caspase-3 expression levels, and the infarct size was measured using Evans blue and tetrazolium chloride staining. The levels of TNF-α and caspase-3 were lower in the S group than in the I/R group, and the myocardial infarct size decreased in the S group. Thus, isoflurane preconditioning in the delayed phase exerted protective effects by decreasing the myocardial caspase-3 expression and TNF-α production in a rabbit model of ischemia-reperfusion injury.

MKP1 inhibits myocardial TNF‐alpha expression and improves cardiac function in endotoxemia

The objective of this study was to investigate the role of mitogen‐activated protein kinase phosphatase‐1 (MKP1) pathway in myocardial tumor necrosis factor (TNF)‐alpha expression and cardiac function during endotoxemia. Experiments were carried out in a mouse model of endotoxemia and in cultured neonatal cardiomyocytes. Lipopolysaccharide (LPS) increased MKP1 expression in the heart and in cultured neonatal cardiomyocytes. LPS‐induced ERK1/2 and p38 phosphorylation in the myocardium was prolonged in MKP1−/− mice. Myocardial TNF‐alpha mRNA and protein levels were enhanced in MKP1−/− compared to WT mice in endotoxemia, leading to a further decrease in cardiac function. Inhibition of Rac1 and PAK1 by a dominant negative Rac1 adenovirus (Ad‐Rac1N17) and PAK1 siRNA, respectively blocked LPS‐induced MKP1 expression in cardiomyocytes. PAK1 siRNA also decreased p38 and c‐Jun N‐terminal kinase (JNK) activation, and TNF‐alpha expression induced by LPS. Furthermore, deficiency in either Rac1 or JNK1 decreased myocardial MKP1 expression in endotoxemic mice. In conclusion, LPS increases myocardial MKP1 expression via JNK1. MKP1 attenuates ERK1/2 and p38 activation, inhibits myocardial TNF‐alpha expression and improves cardiac function in endotoxemia. Thus, MKP1 represents an important negative feedback mechanism limiting pro‐inflammatory response in the heart during sepsis.

Estrogen receptor beta mediates acute myocardial protection following ischemia

Gender differences have been noted in acute ischemia/reperfusion injury. Estrogen and the estrogen receptors (ER) appear to play a critical role in cardiovascular gender differences, given that females have improved myocardial functional recovery associated with decreased tissue inflammation. It has been suggested that ER beta plays a part in decreasing myocardial inflammation following hemorrhage. It remains unknown, however, whether ER beta also may be protective following the more severe insult of complete global, normothermic ischemia/reperfusion injury in the isolated mouse heart. Adult male and female wild-type (WT) and ER beta knockout (ERbKO) mouse hearts were subjected to 20 minutes ischemia and 60 minutes reperfusion (Langendorff model). Myocardial contractile function (+/-dP/dt) was continuously recorded. Heart tissue was analyzed for tumor necrosis factor, interleukin (IL)-1 beta, IL-6, and IL-10 levels as determined by enzyme-linked immunosorbent assay. Females had markedly improved functional recovery compared with males following ischemia/reperfusion. This recovery was associated with lower levels of myocardial tumor necrosis factor, IL-1 beta, and IL-6 in females. However, ERbKO females exhibited significantly less postischemic functional recovery than WT females and were similar to WT males. Interestingly, increased myocardial production of tumor necrosis factor, IL-1 beta, and IL-6 was noted in ERbKO female hearts in response to ischemia/reperfusion. No significant differences were found between male WT and male ERbKO in postischemic functional recovery and proinflammatory cytokine production. ER beta plays a role in the protective effects of estrogen following global, warm ischemia/reperfusion of the isolated mouse heart. This understanding ultimately may enable the development of pharmaceutical agents that harness such protection with minimal collateral sex hormone effects.

Tissue-Specific Effects of the Nuclear Factor κB Subunit p50 on Myocardial Ischemia-Reperfusion Injury

Nuclear factor kappaB (NF-kappaB) is a ubiquitous transcription factor activated by various stimuli implicated in ischemia-reperfusion injury. However, the role of NF-kappaB in cardiac ischemia-reperfusion injury has not yet been well defined. Therefore, we investigated reperfusion damage in mice with targeted deletion of the NF-kappaB subunit p50. Electrophoretic mobility shift assays validated NF-kappaB activation in wild-type (WT) but not p50 knockout (KO) mice. KO and WT animals underwent 30 minutes of coronary artery ligation and 24 hours of reperfusion in vivo. Ischemia-reperfusion damage was significantly reduced in the p50 KO when compared with matching WT mice. Although adhesion molecules such as intercellular adhesion molecule were up-regulated in left ventricles of p50 KO animals, fewer neutrophils infiltrated the infarct area, suggesting leukocytes as a potential mediator of the protection observed in the p50 KO. This was confirmed in adoptive transfer experiments: whereas transplantation of KO bone marrow in KO animals sustained the protective effect on ischemia-reperfusion injury, transplantation of WT bone marrow in KO animals abolished it. Thus, deletion of the NF-kappaB subunit p50 reduces ischemia-reperfusion injury in vivo, associated with less neutrophil infiltration. Bone marrow transplantation experiments indicate that impaired NF-kappaB activation in p50 KO leukocytes attenuates cardiac damage.

P38 Mitogen Activated Protein Kinase Mediates Both Death Signaling and Functional Depression in the Heart

Understanding the myocardial inflammatory response to ischemia is an important part of achieving the elusive clinical goal of long-enduring myocardial protection. p38 mitogen-activated protein kinase (MAPK) has been implicated in oxidant stress-induced myocardial tumor necrosis factor production. However, it is unknown whether p38 MAPK mediates the following important events in both myocardial apoptosis and functional depression: mitogen-activated protein kinase-activated protein kinase 2, caspase-1, caspase-3, and caspase-11 activation, and tumor necrosis factor, interleukin-1beta and interleukin-6 production. Isolated rat hearts were perfused and subjected to an ischemia-reperfusion insult, with and without preischemic infusion of 20 microM SB203580 (p38 MAPK inhibitor). Myocardial functional measurements were continuously recorded throughout the experiments. Myocardial tissue was then assessed for products of p38 MAPK activation, expression of tumor necrosis factor, interleukin-1beta and interleukin-6, and activation of caspase-1, caspase-3 and caspase-11. Postischemic recovery of left ventricular developed pressure, +dP/dt and -dP/dt was significantly increased by p38 MAPK inhibition (MKI) (left ventricular developed pressure: 48.4 +/- 3.87 MKI versus 32.7 +/- 4.32 mm Hg; +dP/dt: 1392.0 +/- 141.7 MKI versus 896.7 +/- 128.5 mm Hg/s; -dP/dt: -889.9 +/- 97.63 MKI versus -548.9 +/- 71.29 mmHg/s). p38 MAPK inhibition also significantly reduced ischemia-reperfusion-induced elevation of left ventricular end-diastolic pressure (82.76 +/- 4.59 MKI vs 69.95 +/- 3.55 mm Hg). p38 MKI decreased myocardial tumor necrosis factor, interleukin-1beta and interleukin-6 protein levels, and reduced active myocardial caspase-1, caspase-3 and caspase-11. The p38 MAPK pathway indeed mediates the following important events in myocardial apoptosis and functional depression: mitogen-activated protein kinase-activated protein kinase 2, caspase-1, caspase-3 and caspase-11 activation, and tumor necrosis factor, interleukin-1beta, interleukin-6 production after myocardial ischemia. Single site (p38 MAPK) inhibition of these events may have important therapeutic implications in myocardial protection.

Simvastatin decreases myocardial tumor necrosis factor α content in heart transplant recipients

Background Statins improve patient survival and decrease rejection episodes in heart transplant recipients. We studied the effects of simvastatin treatment on myocardial tumor necrosis factor α (TNF-α) expression; TNF-α is a potent pro-inflammatory cytokine associated with hypertrophy and fibrosis in heart transplant recipients. Methods We randomized 10 consecutive heart transplant recipients to receive either 20 mg/day simvastatin ( n = 5) or placebo ( n = 5) for 6 months after cardiac transplantation. Routine surveillance endomyocardial biopsy specimens were obtained from all patients. We analyzed tissues for myocardial TNF-α content, total collagen content, and myocyte size using semiquantitative immunohistochemistry. Results Myocyte size and total collagen content of placebo and simvastatin groups did not show a statistically significant difference at any biopsy time point. Myocardium TNF-α content (% tissue area stained) at 1 week after transplantation was similar in the simvastatin and placebo groups. At the 24 th week after transplantation, when compared with Week 1 values, we found a significant decrease in myocardium TNF-α content in the simvastatin group (15.0% ± 2.3% vs 5.8% ± 2.4%, p = 0.02) that was not observed in the placebo group (15.0% ± 1.5% vs 12.0% ± 2.6%, p = not significant). Conclusion Simvastatin treatment in heart transplant recipients decreased myocardium TNF-α expression. This decrease did not translate into a difference in the markers of hypertrophy. However, decreased myocardial TNF-α may be a marker of a general statin-mediated decrease in inflammation in the transplanted heart that leads to improved graft and patient survival.

Simvastatin decreases myocardial tumor necrosis factor-α content in heart transplant recipients

Background: Statins improve patient survival and decrease rejection episodes in heart transplant recipients. We studied the effects of simvastatin treatment on myocardial tumor necrosis factor alpha (TNF- α) expression, a potent pro-inflammatory cytokine associated with hypertrophy and fibrosis in heart transplant recipients.

On-pump coronary artery bypass surgery activates human myocardial NF-κB and increases TNF-α in the heart 1,2

Purpose. Myocardial tumor necrosis factor alpha (TNF) production and nuclear factor kappa B (NF-κB) activation has been demonstrated in chronic heart failure and experimental models of acute ischemia-reperfusion injury. Further, a cause and effect relationship has been established between these events and cardiomyocyte apoptosis following such conditions. It remains unknown, however, whether the myocardial injury associated with coronary artery bypass surgery (CAB) results in myocardial NF-κB activation and TNF production. We hypothesized that CAB with cardiopulmonary bypass (“on-pump”) activates human myocardial NF-κB and increases TNF in the heart. Methods Patients, 18 to 65 years of age, scheduled for elective cardiac surgery but without other preexisting disease were considered eligible for the study. Biopsies of human myocardium were obtained before and after cardiopulmonary bypass and myocardial TNF levels were determined by ELISA and cytotoxicity assay, and NF-κB activation was determined by electrophoretic mobility shift assay ( n = 6 patients). NF-κB activation was quantitated with gel densitometry. Results. The clinical characteristics of the study patients were as follows (means ± SEM): mean age (y) 50.0 ± 5.7, male 6 (100%), cardiopulmonary bypass time (min) 107 ± 37.7, cross-clamp time (min) 68 ± 17.6, number of CAB 3.0 ± 1.1, and length of hospital stay (d) 4.8 ± 0.9. Before CAB, myocardial TNF-α levels were 251 ± 22 pg/g and 33 ± 9 U/g, as determined by ELISA and cytotoxicity assay, respectively. Following CAB, human myocardial TNF-α levels increased to 892 ± 71 pg/g ( P = 0.0008) and 141 ± 11 U/g ( P = 0.0042), as determined by ELISA and cytotoxicity assay, respectively. Before CAB, the ratio of bound to unbound NF-κB DNA was 0.009 ± 0.0007 and after CAB the ratio was 0.24 ± 0.01 ( P < 0.0001). Conclusion. This study represents the initial demonstration that coronary artery bypass grafting results in an activation of NF-κB and an increase of TNF in the heart.

CD14-deficient mice are protected against lipopolysaccharide-induced cardiac inflammation and left ventricular dysfunction.

The molecular mechanisms responsible for sepsis-induced myocardial dysfunction remain undefined. CD14 mediates the inflammatory response to lipopolysaccharide (LPS) in various organs including the heart. In this study we investigated the role of CD14 in LPS-induced myocardial dysfunction in vivo. Wild-type and CD14-deficient (CD14-D) mice were challenged with Escherichia coli LPS. Myocardial tumor necrosis factor, interleukin-1beta (IL-1beta), and NOS2 induction was measured before and 6 hours after LPS challenge. Echocardiographic parameters of left ventricular function were measured before and 6 hours after LPS administration. LPS challenge induced a significant increase in myocardial tumor necrosis factor and IL-1beta mRNA and protein expression in wild-type mice. In contrast, mRNA and protein levels for TNF and IL-1beta were significantly blunted in CD14-D mice. An increase in NOS2 protein was noted within 6 hours of LPS provocation only in the hearts of wild-type mice. This was associated with an increase in ventricular cGMP levels. Activation of nuclear factor-kappaB was observed within 30 minutes of LPS in the hearts of wild-type mice but not in CD14-D mice. In wild-type mice, LPS significantly decreased left ventricular fractional shortening, velocity of circumferential shortening, and dP/dt(max). LPS-treated CD14-D mice maintained normal cardiac function. These results suggest that CD14 is important in mediating the proinflammatory response induced by LPS in the heart and that CD14 is necessary for the development of left ventricular dysfunction during LPS-induced shock in vivo.

Angiotensin II induces tumor necrosis factor biosynthesis in the adult mammalian heart through a protein kinase C-dependent pathway.

Previous studies suggest that angiotensin II (Ang II) upregulates the expression of tumor necrosis factor (TNF) in nonmyocyte cell types; however, the effect of Ang II on TNF expression in the adult mammalian heart is not known. To determine whether Ang II was sufficient to provoke TNF biosynthesis in the adult heart, we examined the effects of Ang II in isolated buffer-perfused Langendorff feline hearts. Ang II (10(-7) mol/L) treatment resulted in a time- and dose-dependent increase in myocardial TNF mRNA and protein biosynthesis in the heart as well as in cultured adult cardiac myocytes. The effects of Ang II on myocardial TNF mRNA and protein synthesis were mediated through the angiotensin type 1 receptor (AT1R), insofar as an AT1R antagonist (AT1a) blocked the effects of Ang II, whereas an angiotensin type 2 receptor (AT2R) antagonist (AT2a) had no effect. Stimulation with Ang II led to the activation of nuclear factor-kappaB and activator protein-1 (AP-1), two transcription factors that are important for TNF gene expression. Nuclear factor-kappaB activation was accompanied by phosphorylation of IkappaBalpha on serine 32 as well as degradation of IkappaBalpha, suggesting that the effects of Ang II were mediated through an IkappaBalpha-dependent pathway. The important role of protein kinase C (PKC) was suggested by studies in which a phorbol ester triggered TNF biosynthesis, and a PKC inhibitor abrogated Ang II-induced TNF biosynthesis. These studies suggest that Ang II provokes TNF biosynthesis in the adult mammalian heart through a PKC-dependent pathway.

Pharmacological stimulation of the cholinergic antiinflammatory pathway.

Efferent activity in the vagus nerve can prevent endotoxin-induced shock by attenuating tumor necrosis factor (TNF) synthesis. Termed the “cholinergic antiinflammatory pathway,” inhibition of TNF synthesis is dependent on nicotinic α-bungarotoxin-sensitive acetylcholine receptors on macrophages. Vagus nerve firing is also stimulated by CNI-1493, a tetravalent guanylhydrazone molecule that inhibits systemic inflammation. Here, we studied the effects of pharmacological and electrical stimulation of the intact vagus nerve in adult male Lewis rats subjected to endotoxin-induced shock to determine whether intact vagus nerve signaling is required for the antiinflammatory action of CNI-1493. CNI-1493 administered via the intracerebroventricular route was 100,000-fold more effective in suppressing endotoxin-induced TNF release and shock as compared with intravenous dosing. Surgical or chemical vagotomy rendered animals sensitive to TNF release and shock, despite treatment with CNI-1493, indicating that an intact cholinergic antiinflammatory pathway is required for antiinflammatory efficacy in vivo. Electrical stimulation of either the right or left intact vagus nerve conferred significant protection against endotoxin-induced shock, and specifically attenuated serum and myocardial TNF, but not pulmonary TNF synthesis, as compared with sham-operated animals. Together, these results indicate that stimulation of the cholinergic antiinflammatory pathway by either pharmacological or electrical methods can attenuate the systemic inflammatory response to endotoxin-induced shock.

Myocardial tumor necrosis factor–α expression does not correlate with clinical indices of heart failure in patients on left ventricular assist device support

Background. Mechanical unloading with a left ventricular assist device (LVAD) can improve clinical indices of heart failure and alter myocardial tumor necrosis factor–α (TNFα) expression, but a correlation between clinical and molecular indices has not been established. Methods. We enrolled 14 patients with end-stage heart failure treated with drugs and mechanical unloading in a protocol including the collection of myocardial tissue samples at LVAD implantation and explantation. Ten nonfailing donor hearts served as controls. TNFα expression was measured by quantitative reverse transcription polymerase chain reaction. Clinical indices of heart failure were retrospectively analyzed and correlated with myocardial TNFα expression. Results. Left ventricular end-diastolic dimension decreased ( p < 0.01) and cardiac index ( p < 0.001) increased with unloading. Abnormal values of serum sodium, creatinine, blood urea nitrogen, glutamic-oxaloacetic transaminase, glutamic-pyruvic transaminase, and albumin showed a trend toward normalization with mechanical unloading. TNFα expression was increased in 5 of 14 patients and decreased with mechanical unloading in 4 of them. Surprisingly, there was no correlation between mRNA levels of TNFα and any of the clinical indices studied. Conclusions. Although clinical indices of heart failure improve and elevated levels of myocardial TNFα expression decrease with mechanical unloading, there is no correlation between the two. Thus, clinical and molecular indices of heart failure in LVAD-supported patients do not always correlate.

Beta-adrenergic blockade in developing heart failure: effects on myocardial inflammatory cytokines, nitric oxide, and remodeling.

Whether beta-adrenergic blockade modulates myocardial expression of inflammatory cytokines and nitric oxide (NO) in heart failure is unclear. We administered oral metoprolol or no therapy to rats for 12 weeks after large myocardial infarction and subsequently examined left ventricular (LV) remodeling; myocardial tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6 expression; and NO. In untreated rats, echocardiography revealed significant (P<0.001) LV dilatation and systolic dysfunction compared with sham. Papillary muscle studies revealed isoproterenol hyporesponsiveness to be unaltered by NO synthase (NOS) inhibition. Circulating NO metabolites were undetectable. In noninfarcted myocardium, although inducible NOS (iNOS) mRNA was absent, TNF-alpha, IL-1beta, and IL-6 mRNA and protein were markedly elevated compared with sham (P<0.001), with 2-fold higher expression (P<0.025) of IL-6 compared with TNF-alpha or IL-1beta. Metoprolol administration starting 48 hours after infarction (1) attenuated (P<0.02) LV dilatation and systolic dysfunction, (2) preserved isoproterenol responsiveness (P<0.025) via NO-independent mechanisms, and (3) reduced myocardial gene expression and protein production of TNF-alpha and IL-1beta (P<0. 025) but not IL-6, which remained high. During heart failure development, adrenergic activation contributes to increased myocardial expression of TNF-alpha and IL-1beta but not IL-6, and one mechanism underlying the beneficial effects of beta-adrenergic blockade may involve attenuation of TNF-alpha and IL-1beta expression independent of iNOS and NO.

Myocardial tumor necrosis factor-alpha secretion in hypertensive and heart failure-prone rats.

Acute increases in blood pressure (BP) increase myocardial tumor necrosis factor (TNF)-alpha production, but it is not known whether chronic hypertensive stress elevates myocardial TNF-alpha production, possibly contributing to cardiac remodeling, decreased cardiac function, and faster progression to heart failure. BP, cardiac function, and size were evaluated in normotensive [Sprague-Dawley (SD)], spontaneously hypertensive (SHR), and spontaneously hypertensive heart failure-prone (SHHF) rats at 6, 12, 15, and 18 mo of age and in failing SHHF. Left ventricular tissues were evaluated for secretion of bioactive TNF-alpha and inhibition of TNF-alpha secretion by phosphodiesterase inhibitors. All ventricles secreted bioactive and immunoreactive TNF-alpha, but secretion decreased with age. SHR and SHHF rats secreted more TNF-alpha than SD rats at 6 mo of age, but only failing SHHF rats secreted significantly more TNF-alpha at 18 mo. Amrinone inhibited TNF-alpha secretion in all rats and was less potent but more efficacious than RO-201724 in all strains. TNF-alpha secretion correlated with BP and left ventricular mass in 6-mo-old rats, but this relationship disappeared with age. Results suggest that hypertension and/or cardiac remodeling is associated with elevated myocardial TNF-alpha, and, although hypertension, per se, did not maintain elevated cardiac TNF-alpha levels, SHHF rats increase TNF-alpha production during the end stages of failure.

Hydrogen peroxide induces tumor necrosis factor α–mediated cardiac injury by a P38 mitogen-activated protein kinase–dependent mechanism

Background: Oxidant stress caused by ischemia or endotoxemia induces myocardial dysfunction and cardiomyocyte death; however, mechanisms responsible remain unknown. We hypothesized that hydrogen peroxide (H 2O 2) induces myocardial dysfunction and cardiomyocyte death via P38 mitogen-activated protein kinase (MAPK)–mediated myocardial tumor necrosis factor (TNF) production. Methods: Langendorff perfused rat hearts (6/group) were subjected to oxidant stress (H 2O 2 infusion; 300 mmol/L × 80 minutes), with and without prior infusion of a specific P38 kinase MAPK inhibitor (P38i = 1 mmol/L/min × 5 minutes) or TNF neutralization (20 mg TNF binding protein (BP)/min × 80 minutes). Developed pressure (DP), coronary flow, and end-diastolic pressure were continuously recorded. Myocardial creatine kinase (CK) loss was measured in the coronary effluent, and tissue TNF was measured in myocardial homogenates. Results: Eighty minutes of H 2O 2 infusion induced a 6.5-fold increase in myocardial TNF production, which was associated with a 70% decrease in DP and increase in CK loss. P38 MAPK inhibition or TNF-BP decreased myocardial TNF production, cardiomyocyte death, and myocardial dysfunction. Conclusions: These results demonstrate that H 2O 2 alone induces myocardial TNF production. P38 MAPK is an oxidant-sensitive enzyme that mediates oxidant-induced myocardial TNF production, cardiac dysfunction, and cardiomyocyte death. (Surgery 1998;124:291-7.)

Hydrogen peroxide induces tumor necrosis factor alpha-mediated cardiac injury by a P38 mitogen-activated protein kinase-dependent mechanism.

Oxidant stress caused by ischemia or endotoxemia induces myocardial dysfunction and cardiomyocyte death; however, mechanisms responsible remain unknown. We hypothesized that hydrogen peroxide (H2O2) induces myocardial dysfunction and cardiomyocyte death via P38 mitogen-activated protein kinase (MAPK)-mediated myocardial tumor necrosis factor (TNF) production. Langendorff perfused rat hearts (6/group) were subjected to oxidant stress (H2O2 infusion; 300 mmol/L x 80 minutes), with and without prior infusion of a specific P38 kinase MAPK inhibitor (P38i = 1 mmol/L/min x 5 minutes) or TNF neutralization (20 mg TNF binding protein (BP)/min x 80 minutes). Developed pressure (DP), coronary flow, and end-diastolic pressure were continuously recorded. Myocardial creatine kinase (CK) loss was measured in the coronary effluent, and tissue TNF was measured in myocardial homogenates. Eighty minutes of H2O2 infusion induced a 6.5-fold increase in myocardial TNF production, which was associated with a 70% decrease in DP and increase in CK loss. P38 MAPK inhibition or TNF-BP decreased myocardial TNF production, cardiomyocyte death, and myocardial dysfunction. These results demonstrate that H2O2 alone induces myocardial TNF production. P38 MPAK is an oxidant-sensitive enzyme that mediates oxidant-induced myocardial TNF production, cardiac dysfunction, and cardiomyocyte death.

Tumor necrosis factor in the heart.

The heart is a tumor necrosis factor (TNF)-producing organ. Both myocardial macrophages and cardiac myocytes themselves synthesize TNF. Accumulating evidence indicates that myocardial TNF is an autocrine contributor to myocardial dysfunction and cardiomyocyte death in ischemia-reperfusion injury, sepsis, chronic heart failure, viral myocarditis, and cardiac allograft rejection. Indeed, locally (vs. systemically) produced TNF contributes to postischemic myocardial dysfunction via direct depression of contractility and induction of myocyte apoptosis. Lipopolysaccharide or ischemia-reperfusion activates myocardial P38 mitogen-activated protein (MAP) kinase and nuclear factor kappa B, which lead to TNF production. TNF depresses myocardial function by nitric oxide (NO)-dependent and NO-independent (sphingosine dependent) mechanisms. TNF activation of TNF receptor 1 or Fas may induce cardiac myocyte apoptosis. MAP kinases and TNF transcription factors are feasible targets for anti-TNF (i.e., cardioprotective) strategies. Endogenous anti-inflammatory ligands, which trigger the gp130 signaling cascade, heat shock proteins, and TNF-binding proteins, also control TNF production and activity. Thus modulation of TNF in cardiovascular disease represents a realistic goal for clinical medicine.