Eicosanoid signalling pathways in the heart

Abstract

Myocardial phospholipids serve as primary reservoirs of arachidonic acid (AA), which is liberated through the rate-determining hydrolytic action of cardiac phospholipases A2 (PLA2s). A predominant PLA2 in myocardium is calcium-independent phospholipase A2beta (iPLA2beta), which, through its calmodulin (CaM) and ATP-binding domains, is regulated by alterations in local cellular Ca2+ concentrations and cardiac bioenergetic status, respectively. Importantly, iPLA2beta has been demonstrated to be activated by ischaemia through elevation of the concentration of myocardial fatty acyl-CoA, which abrogates Ca2+/CaM-mediated inhibition of iPLA2beta. AA released by PLA2-catalysed hydrolysis of phospholipids serves as a precursor for eicosanoids generated by pathways dependent on cyclooxygenases (COX), lipoxygenases (LOX), and cytochromes P450 (CYP). Eicosanoids initiate and propagate diverse signalling cascades, primarily through their interaction with cellular receptors and ion channels. However, during pathologic states such as ischaemia or congestive heart failure, eicosanoids contribute to multiple maladaptive changes including inflammation, alterations of cellular growth programmes, and activation of multiple transcriptional events leading to the deleterious sequelae of these pathologic states. This review summarizes the central roles of myocardial PLA(2)s in eicosanoid signalling in the heart, the major COX, LOX, and CYP pathways of eicosanoid generation in the myocardium, and the effects of important eicosanoids on receptor-, ion channel-, and transcription-mediated processes that facilitate cardiac hypertrophy, mediate ischaemic preconditioning, and precipitate arrhythmogenesis in response to pathologic stimuli.

Highly potent visnagin derivatives inhibit Cyp1 and prevent doxorubicin cardiotoxicity

“…CYP1 enzymes also play an important role in the metabolism of endogenous bioactive polyunsaturated fatty acids (27), such as the hydroxyeicosatetraenoic acids (HETEs). HETEs are arachidonic acid metabolites that have been previously implicated in the pathogenesis of DOX cardiotoxicity (28) and other cardiovascular diseases such as hypertension (29). It is possible that CYP1 inhibitors such as C1 and its analogs prevent the generation of cardiotoxic metabolites such as those downstream of DOX or the HETEs in order to protect against DOX cardiomyopathy.…”

Calcium-independent phospholipases A2 and their roles in biological processes and diseases

“…Considering generate eicosanoids ( 97,125,245,264 ). These bioactive lipids act as paracrine and autocrine factors and greatly contribute to infl ammation (264)(265)(266) and autoimmune diseases (267)(268)(269)(270)(271)(272)(273)(274). PGE 2 has been reported to reduce debris clearance ( 275 ), and apoptotic clearance defects in non-obese diabetic (NOD) macrophages and dendritic cells are attributed to high PGE 2 levels ( 276,277 ).…”

“…The myocardial 40 kDa iPLA 2 , described as a plasmalogen-selective PLA 2 ( 3, 118 ), was inhibited by BEL ( 146 ), stabilized by ATP ( 117 ), and formed an oligomeric regulatory complex with phosphofructokinase ( 384 ). From the collection of related studies, it can be ascertained that iPLA 2 ␤ activation in the heart may be benefi cial and also detrimental ( 265,385,386 ). For instance, increases in membrane-iPLA 2 ( 387 ) and mitochondrial-iPLA 2 ( 388 ) activities were associated with irreversible cell damage mutations and combination of mutations in PLA2G6 -associated neurodegeneration may be associated with Parkinson's and Alzheimer's diseases in the absence or presence of iron accumulations ( 316,(339)(340)(341)(342)(343)(344)(345)(346)(347).…”

Genetic Ablation of Calcium-independent Phospholipase A2γ Leads to Alterations in Hippocampal Cardiolipin Content and Molecular Species Distribution, Mitochondrial Degeneration, Autophagy, and Cognitive Dysfunction

“…PLA 2 s catalyze the cleavage of acyl groups from glycerophospholipids, generating free fatty acids and lysophospholipids, thereby initiating dual pathways of signal transduction (10). The released polyunsaturated fatty acids can be further metabolized to numerous biologically active lipid second messengers with discrete biologic functions * This work was supported, in whole or in part, by National Institutes of Health (11,12). Moreover, the production of lysolipids initiates a parallel arm of this signaling pathway through regulating the electrophysiologic properties of neuronal membranes, modulating capacitative calcium influx and serving as precursors of signaling lipids such as platelet-activating factor and lysophosphatidic acid (13,14).…”