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

Abstract

]i transients and contraction with electrically stimulated adult rat cardiac myocytes. At a low concentration (10 ng/ml) TNF-␣ produced a 40% increase in the amplitude of both [Ca 2ϩ ]i transients and contraction within 40 min. At a high concentration (50 ng/ml) TNF-␣ 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 [Ca 2ϩ ]i transients and contraction after 30 min. Both the positive and negative effects of TNF-␣ were reproduced by AA and blocked by arachidonyltrifluoromethyl ketone (AACOCF3), an inhibitor of cytosolic PLA2. Lipoxygenase and cyclooxygenase inhibitors reproduced the highdose effects of TNF-␣ and AA. The negative effects of TNF-␣ 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-␣.heart; cytosolic Ca 2ϩ -dependent phospholipase A2; ceramidase; sphingosine

Tumor Necrosis Factor-.ALPHA. Downregulates the Voltage Gated Outward K+ Current in Cultured Neonatal Rat Cardiomyocytes A Possible Cause of Electrical Remodeling in Diseased Hearts

“…14,15 TNFmodulates cardiac function through a number of signaling pathways, including cross-talk to the renin -angiotensin pathway or -adrenergic pathway, and it also induces cardiac hypertrophy. [5][6][7][17][18][19][20][21][22][23][24] Although the precise mechanisms of TNF--induced regulation of the K + channels are unknown, the cellular hypertrophy and subsequent intracellular Ca 2+ -overload might modulate the K + channels' gene expression by activating the calcineurin/NFATc3 pathway. 14 On the other hand, the change in the ion channel is not necessarily an outcome but may be also a cause of cellular hypertrophy.…”

“…sentative proinflammatory cytokine, in altering Ca + handling, which may lead to cellular hypertrophy as well as toxicity of the myocardium, [3][4][5][6][7][8][9][10] its effect on the cardiac K + channels is still unknown. In the present study, we evaluated the effect of TNF-on the function and expression of these channels and their related molecules as well as on cellular hypertrophy in cultured neonatal rat cardiomyocytes.…”

Neutral sphingomyelinase inhibition participates to the benefits of N-acetylcysteine treatment in post-myocardial infarction failing heart rats

“…In its both reduced (GSH) and oxidized (GSSG) forms, glutathione serves as a natural inhibitor of N-SMase [25], which hydrolyzes sphingomyelin into ceramide, controlling the sphingolipid signaling cascade [26][27][28] and mediating TNF-α apoptotic [29] and negative inotropic effects in cardiomyocytes [11,30,31]. Downstream ceramide generation, the ordered cascade of events in N-SMase pathway comprises downregulation of the prosurvival factor Bcl-2, resulting into a decrease of the proapoptotic Bax/ prosurvival Bcl-2 protein ratio that in turn elicits activation of caspase-3 [32].…”

The cyclooxygenase-2 product prostaglandin E2 modulates cardiac contractile function in adult rat ventricular cardiomyocytes

“…The signaling mechanism involved in the cardiac response of PGE 2 is rather complex and largely unclear. Up to date, the physiological effects of PGE 2 are believed to be carried out through the G protein-coupled E type prostaglandin receptors EP 1 , EP 2 , EP 3 and EP 4 . The cardiac contractile response of PGE 2 in ventricular myocyte is expected to depend on one or more of these receptors with distinct signal transduction pathway(s) associated with each individual receptor subtypes [7].…”

“…Two COX isoforms, namely COX-1 and COX-2, have been found in mammalian cells with COX-1 being constitutively expressed and COX-2 being normally absent and inducible by various stimuli such as inflammatory cytokines [1,2]. Both prostaglandins and arachidonic acid are believed to participate in multiple physiological as well as pathophysiological responses such as reproductive, immunological, endocrine, tumorigenesis and cardiovascular regulation [1][2][3][4]. Arachidonic acid, the precursor for eicosanoid formation, is released in response to receptor activation and pathological stimuli such as my-ocardial ischemia.…”