Arachidonic acid mediates dual effect of TNF-α on Ca2+ transients and contraction of adult rat cardiomyocytes

2002 ◽  
Vol 282 (6) ◽  
pp. C1339-C1347 ◽  
Author(s):  
Aïssata Amadou ◽  
Artur Nawrocki ◽  
Martin Best-Belpomme ◽  
Catherine Pavoine ◽  
Françoise Pecker
Keyword(s):  
Arachidonic Acid ◽  
Cyclooxygenase Inhibitors ◽  
High Dose ◽  
Negative Effects ◽  
Dual Effect ◽  
Rat Cardiomyocytes ◽  
Adult Rat ◽  
Tnf Α ◽  
Biphasic Effect

Tumor necrosis factor (TNF)-α has a biphasic effect on heart contractility and stimulates phospholipase A2 (PLA2) in cardiomyocytes. Because arachidonic acid (AA) exerts a dual effect on intracellular Ca2+ concentration ([Ca2+]i) transients, we investigated the possible role of AA as a mediator of TNF-α on [Ca2+]i transients and contraction with electrically stimulated adult rat cardiac myocytes. At a low concentration (10 ng/ml) TNF-α produced a 40% increase in the amplitude of both [Ca2+]i transients and contraction within 40 min. At a high concentration (50 ng/ml) TNF-α evoked a biphasic effect comprising an initial positive effect peaking at 5 min, followed by a sustained negative effect leading to 50–40% decreases in [Ca2+]i transients and contraction after 30 min. Both the positive and negative effects of TNF-α were reproduced by AA and blocked by arachidonyltrifluoromethyl ketone (AACOCF3), an inhibitor of cytosolic PLA2. Lipoxygenase and cyclooxygenase inhibitors reproduced the high-dose effects of TNF-α and AA. The negative effects of TNF-α and AA were also reproduced by sphingosine and were abrogated by the ceramidase inhibitor n-oleoylethanolamine. These results point out the key role of the cytosolic PLA2/AA pathway in mediating the contractile effects of TNF-α.

The Anti-Inflammatory Potential of Mimosa caesalpiniifolia Following Experimental Colitis: Role of COX-2 and TNF-Alpha Expression

Drug Research ◽  
2017 ◽  
Vol 68 (04) ◽  
pp. 196-204 ◽  
Author(s):  
Marcelo Silva ◽  
Wagner Vilegas ◽  
Marcelo da Silva ◽  
Ana Paiotti ◽  
Mauricio Pastrelo ◽  
...  
Keyword(s):  
Protective Action ◽  
Experimental Colitis ◽  
Distal Colon ◽  
Tnf Alpha ◽  
High Dose ◽  
Dependent Manner ◽  
Hydroalcoholic Extract ◽  
Tnf Α ◽  
Cox 2

AbstractThe aim of this study was to evaluate the preventive and/or protective action of Mimosa caesalpiniifolia (M. caesalpiniifolia) following experimental colitis in rats. The rats were randomized into ten groups (n=10 per group), as follows: G1 – Sham group:; G2 – TNBS group; G3, G4 –colitis and treated with hydroalcoholic extract of M. caesalpiniifolia 250 mg/kg/day after and before/after inducing colitis, respectively; G5, G6 – colitis and treated with hydroalcoholic extract of M. caesalpiniifolia at 125 mg/kg/day after and before/after inducing colitis respectively; G7,G8 – colitis and treated with ethylacetate fraction of M. caesalpiniifolia at 50 mg/kg/day after and before/after inducing colitis, respectively; G9,G10 – colitis and treated with ethylacetate fraction of M. caesalpiniifolia at 50 mg/kg/day after and before/after inducing colitis, respectively. Rats treated with hydroalcoholic extract of M. caesalpiniifolia for both doses showed lower tissue damage in the distal colon. Ethylacetate fraction was effective at the highest dose only when administrated after inducing colitis. A downregulation of COX-2 was detected to rats suffering colitis and treated with M. caesalpiniifolia at high dose. On the other hand, TNF-alpha immunoexpression decreased in groups treated with M. caesalpiniifolia at low dose after inducing colitis. In summary, our results suggest that M. caesalpiniifolia attenuated the lesions of the colon, reduced inflammation, and modulates the expression of COX-2 and TNF-α during chronic colitis induced by TNBS when using for therapeutic purposes on a dose-dependent manner.

scholarly journals Autophagy and protein kinase C are required for cardioprotection by sulfaphenazole

2010 ◽  
Vol 298 (2) ◽  
pp. H570-H579 ◽  
Author(s):  
Chengqun Huang ◽  
Wayne Liu ◽  
Cynthia N. Perry ◽  
Smadar Yitzhaki ◽  
Youngil Lee ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Enhanced Recovery ◽  
Ischemia Reperfusion ◽  
Dominant Negative ◽  
Rat Cardiomyocytes ◽  
Adult Rat ◽  
Kinase C ◽  
Rat Hearts

Previously, we showed that sulfaphenazole (SUL), an antimicrobial agent that is a potent inhibitor of cytochrome P4502C9, is protective against ischemia-reperfusion (I/R) injury (Ref. 15 ). The mechanism, however, underlying this cardioprotection, is largely unknown. With evidence that activation of autophagy is protective against simulated I/R in HL-1 cells, and evidence that autophagy is upregulated in preconditioned hearts, we hypothesized that SUL-mediated cardioprotection might resemble ischemic preconditioning with respect to activation of protein kinase C and autophagy. We used the Langendorff model of global ischemia to assess the role of autophagy and protein kinase C in myocardial protection by SUL during I/R. We show that SUL enhanced recovery of function, reduced creatine kinase release, decreased infarct size, and induced autophagy. SUL also triggered PKC translocation, whereas inhibition of PKC with chelerythrine blocked the activation of autophagy in adult rat cardiomyocytes. In the Langendorff model, chelerythrine suppressed autophagy and abolished the protection mediated by SUL. SUL increased autophagy in adult rat cardiomyocytes infected with GFP-LC3 adenovirus, in isolated perfused rat hearts, and in mCherry-LC3 transgenic mice. To establish the role of autophagy in cardioprotection, we used the cell-permeable dominant-negative inhibitor of autophagy, Tat-Atg5K130R. Autophagy and cardioprotection were abolished in rat hearts perfused with recombinant Tat-Atg5K130R. Taken together, these studies indicate that cardioprotection mediated by SUL involves a PKC-dependent induction of autophagy. The findings suggest that autophagy may be a fundamental process that enhances the heart's tolerance to ischemia.

Dual effect of heparin on cultured adult rat cardiomyocytes

2004 ◽  
Vol 92 (6) ◽  
pp. 1212-1220
Author(s):  
Nebil Rezgui ◽  
Corda Stefano ◽  
Marotte Françoise ◽  
Samuel Jane-Lise
Keyword(s):  
Dual Effect ◽  
Rat Cardiomyocytes ◽  
Adult Rat

scholarly journals Role of Prostaglandins in Blood-Induced Vasoconstriction of Canine Cerebral Arteries

1988 ◽  
Vol 8 (1) ◽  
pp. 109-115 ◽  
Author(s):  
Sally A. Lang ◽  
Michael B. Maron
Keyword(s):  
Arachidonic Acid ◽  
Vascular Resistance ◽  
Topical Application ◽  
Cerebral Arteries ◽  
Cyclooxygenase Inhibitors ◽  
Prostaglandin E ◽  
Constant Flow ◽  
Thromboxane Synthetase ◽  
By Products

We tested the hypothesis that the vasoconstriction produced by the application of blood to the adventitial surfaces of the vessels of an isolated perfused canine circle of Willis preparation was mediated by products of prostaglandin metabolism. In this preparation (perfused at constant flow and outflow pressure), topical application of blood produced an average 16.6 ± 1.8 (SE) mm Hg increase in inflow pressure. This response could be prevented with four structurally dissimilar cyclooxygenase inhibitors (aspirin, indomethacin, ibuprofen, and meclofenamate), suggesting that the blood-induced increase in vascular resistance was mediated by prostaglandins. Imidazole, an inhibitor of thromboxane synthetase, had no effect on the blood response. Further support for the involvement of prostaglandins in this response was provided by additional experiments in which either arachidonic acid, prostaglandin E2 (PGE2), or PGF2α were administered. All three treatments produced vasoconstriction. These results suggest that the vessels of this preparation are capable of synthesizing vasoconstrictor prostaglandins and indicate that they are reactive to known vasoactive prostaglandins.

scholarly journals Mast cells are necessary for the hypothermic response to LPS-induced sepsis

2009 ◽  
Vol 296 (3) ◽  
pp. R595-R602 ◽  
Author(s):  
Katherine M. Nautiyal ◽  
Heather McKellar ◽  
Ann-Judith Silverman ◽  
Rae Silver
Keyword(s):  
Mast Cells ◽  
Low Frequency ◽  
High Dose ◽  
Brain Site ◽  
Hypothermic Response ◽  
Tnf Α ◽  
Sepsis Induction ◽  
Baseline Temperature ◽  
Ifn Γ

As central nervous system residents, mast cells contain many cytokines and are localized primarily near large blood vessels in the diencephalon and within the leptomeninges, making them candidates for immune to neural “cross talk.” Using mast cell-deficient KitW-sh/W-sh mice, we assessed the role of these cells in the thermoregulatory component of the immune response to lipopolysaccharide (LPS). KitW-sh/W-sh and wild-type (WT) mice differed in several respects in response to injection of a high dose of LPS (1 mg/kg ip). Core temperature (Tc) of WT mice decreased by ∼3°C, whereas KitW-sh/W-sh mice did not become hypothermic but instead exhibited pronounced low-frequency Tc oscillations around their baseline temperature. In addition, KitW-sh/W-sh mice had lower levels of whole brain TNF-α but no differences in IL-1β, IL-6, IFN-γ, or histamine compared with WT mice following injection of the high dose of LPS, consistent with the role of TNF-α in sepsis. KitW-sh/W-sh mice had increased resistance to LPS, and some survived a dose of LPS that was lethal in littermate controls. In contrast, KitW-sh/W-sh and WT mice were similar in other aspects, namely, in the hyperthermia following injection of TNF-α (1.5 μg icv), reduced nighttime Tc and locomotor activity (to 1 mg/kg LPS), response to a low dose of LPS (10 μg/kg ip), and response to subcutaneous turpentine injection. These results indicate that mast cells play a role in the regulation of thermoregulatory responses and survival following sepsis induction and suggest a brain site of action.

Inhibition of NHE protects reoxygenated cardiomyocytes independently of anoxic Ca2+ overload and acidosis

2000 ◽  
Vol 279 (5) ◽  
pp. H2143-H2150 ◽  
Author(s):  
C. Schäfer ◽  
Y. V. Ladilov ◽  
M. Schäfer ◽  
H. M. Piper
Keyword(s):  
Intracellular Ph ◽  
Cytosolic Ph ◽  
Bicarbonate Buffer ◽  
Rat Cardiomyocytes ◽  
Hepes Buffer ◽  
Adult Rat ◽  
Reoxygenation Injury ◽  
Sodium Binding ◽  
Cytosolic Acidification

We investigated the question of whether inhibition of the Na+/H+ exchanger (NHE) during ischemia is protective due to reduction of cytosolic Ca2+ accumulation or enhanced acidosis in cardiomyocytes. Additionally, the role of the Na+-HCO3 − symporter (NBS) was investigated. Adult rat cardiomyocytes were exposed to simulated ischemia and reoxygenation. Cytosolic pH [2′,7′-bis(2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF)], Ca2+ (fura 2), Na+ [sodium-binding benzolfuran isophthatlate (SBFI)], and cell length were measured. NHE was inhibited with 3 μmol/l HOE 642 or 1 μmol/l 5-( N-ethyl- N-isopropyl)-amiloride (EIPA), and NBS was inhibited with HEPES buffer. During anoxia in bicarbonate buffer, cells developed acidosis and intracellular Na and Ca (Nai and Cai, respectively) overload. During reoxygenation cells underwent hypercontracture (44.0 ± 4.1% of the preanoxic length). During anoxia in bicarbonate buffer, inhibition of NHE had no effect on changes in intracellular pH (pHi), Nai, and Cai, but it significantly reduced the reoxygenation-induced hypercontracture (HOE: 61.0 ± 1.4%, EIPA: 68.2 ± 1.8%). The sole inhibition of NBS during anoxia was not protective. We conclude that inhibition of NHE during anoxia protects cardiomyocytes against reoxygenation injury independently of cytosolic acidification and Cai overload.

TNF-alpha protects from exacerbated autoinflammatory response in mouse model of experimental autoimmune myocarditis

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
F Rolski ◽  
K Weglarczyk ◽  
P Pelczar ◽  
M Siedlar ◽  
B Ludewig ◽  
...  
Keyword(s):  
T Cells ◽  
High Dose ◽  
Wild Type ◽  
Autoimmune Myocarditis ◽  
Heart Failure Patients ◽  
Tnf Α ◽  
Intercellular Adhesion Molecules ◽  
Experimental Autoimmune Myocarditis ◽  
Experimental Autoimmune

Abstract Background Myocarditis is an inflammatory heart disease and heart-specific autoimmunity plays an important role in development and progression of the disease. TNF-α is a potent pro-inflammatory cytokine implicated in pathogenesis in many inflammatory diseases. Unexpectedly, clinical studies showed that high dose anti-TNF-α therapy increased hospitalization and mortality of heart failure patients. Purpose To elucidate the role of TNF-α in heart-specific autoimmunity and in activation of cardiac microvascular endothelial cells in autoimmune response. Methods Experimental autoimmune myocarditis (EAM) was induced in BALB/c mice by immunization with α-myosin heavy chain peptide (α-MyHC) together with complete Freund's adjuvant. Development of myocarditis in the absence of adjuvant was analysed in TCR-M mice, which CD4+ T cells expressed transgenic T cell receptor recognizing α-MyHC. The role of TNF-α was addressed using haploinsufficient Tnf+/−, knockout Tnf−/− and TCR-M x Tnf+/− mice. Effects of antigen-dependent T cell response on cardiac microvascular endothelial cell (cMVEC) activation were assessed by flow cytometry, immunoblotting and leukocyte-endothelium adhesion assay. Inflammatory cells were phenotyped using flow cytometry, cytokine production was measured by ELISA. Results EAM induction resulted in reduced prevalence of myocarditis in Tnf+/− and Tnf−/− comparing wild-type mice at day 21 after disease induction. However, Tnf+/− and Tnf−/− mice that developed myocarditis showed higher severity of the disease than wild-type controls. On the other hand, TCR-M x Tnf+/− mice showed exacerbated myocarditis at age of 2 months and were characterized by increased mortality comparing with TCR-M controls. TCR-M Tnf+/− mice showed increased total number of cardiac infiltrates compared to TCR-M controls, but no difference in myeloid subsets were observed. In contrast, Tnf+/− and Tnf−/− mice showed significantly increased percentage of T effector cells in spleens and blood in both myocarditis models. Stimulation with rTNF-α induced expression of intercellular adhesion molecules (ICAM1, VCAM1 and P-selectin) on cMVECs, which was associated with increased ability to bind leukocytes under shear flow conditions. TNF-α deficiency had, however, no impact on antigen-specific activation and proliferation of T-cells. Medium conditioned of antigen-activated wild-type, Tnf+/− and Tnf−/− CD4+ T cells showed similar cMVEC activation measured by increased expression of intercellular adhesion molecules and binding of leukocytes under shear flow condition. Furthermore, Tnf+/− and Tnf−/m- myeloid cells showed increased production of IL-6. Conclusions Our data suggest that TNF-α protects the heart from excessive autoimmune reaction by suppressing expansion of autoreactive effector T cells. Thus, this study uncovers a cardioprotective role of proinflammatory TNF-α and potentially can explain the deleterious effect of high dose anti-TNF-α therapy in heart failure patients. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): The National Science Centre Poland

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