Unraveling the Role of 12- and 20- HETE in Cardiac Pathophysiology: G-Protein–Coupled Receptors, Pharmacological Inhibitors, and Transgenic Approaches

Abstract

:Arachidonic acid–derived lipid mediators play crucial roles in the development and progression of cardiovascular diseases. Eicosanoid metabolites generated by lipoxygenases and cytochrome P450 enzymes produce several classes of molecules, including the epoxyeicosatrienoic acid (EET) and hydroxyeicosatetraenoic acids (HETE) family of bioactive lipids. In general, the cardioprotective effects of EETs have been documented across a number of cardiac diseases. In contrast, members of the HETE family have been shown to contribute to the pathogenesis of ischemic cardiac disease, maladaptive cardiac hypertrophy, and heart failure. The net effect of 12(S)- and 20-HETE depends upon the relative amounts generated, ratio of HETEs:EETs produced, timing of synthesis, as well as cellular and subcellular mechanisms activated by each respective metabolite. HETEs are synthesized by and affect multiple cell types within the myocardium. Moreover, cytochrome P450–derived and lipoxygenase- derived metabolites have been shown to directly influence cardiac myocyte growth and the regulation of cardiac fibroblasts. The mechanistic data uncovered thus far have employed the use of enzyme inhibitors, HETE antagonists, and the genetic manipulation of lipid-producing enzymes and their respective receptors, all of which influence a complex network of outcomes that complicate data interpretation. This review will summarize and integrate recent findings on the role of 12(S)-/20-HETE in cardiac diseases.

Free fatty acid receptor 4 (FFAR4) regulates cardiac oxylipin balance to promote inflammation resolution in a model of heart failure preserved ejection fraction secondary to metabolic syndrome

“…Furthermore, loss of Ffar4 increased 12-HETE levels, increasing the 12-HETE/18-HEPE ratio, and suggesting a more pro-inflammatory state in the male Ffar4KO heart both at baseline and in response to the HFpEF-MetS diet. In the heart, prior studies indicate that 12-HETE worsens ischemic injury, induces maladaptive hypertrophy, and worsens HF (60), and a recent study indicated that 12-HETE specifically worsens HFpEF remodeling (44). Ultimately, the increased 12-HETE/18-HEPE ratio in male Ffar4KO hearts was associated with an altered immune response, with increased CD64 + macrophage numbers, which correlated with worsened HFpEF remodeling.…”

Activation of GPR75 Signaling Pathway Contributes to the Effect of a 20-HETE Mimetic, 5,14-HEDGE, to Prevent Hypotensive and Tachycardic Responses to Lipopolysaccharide in a Rat Model of Septic Shock

“…1–5 20-HETE has been implicated in the maintenance of physiological functions of vital organs, including the heart, lung, kidney, and brain, and in the pathogenesis of a wide variety of diseases including hypertension, atherosclerosis, tissue injury, inflammation, sepsis, and septic shock. 6–13 The results of several studies emphasize that 20-HETE has also pro- and antihypertensive effects and pro- and anti-inflammatory properties. 12,14–18…”

“…In recent years, new compounds that act as 20-HETE mimetics and antagonists have been synthesized and extensively examined in preclinical studies for indications, such as hypertension and inflammation. 6,9 A 20-HETE mimetic, 5,14-HEDGE, is reported to show improved stability in vitro compared with 20-HETE, due to its glycine substitution and absence of double bonds preventing its degradation by β-oxidation and cyclooxygenase. 31 We have previously shown that enhanced expression of CYP4A1 and 20-HETE synthesis contributes to the protective effect of a 20-HETE mimetic, N -(20-hydroxyeicosa-5[Z],14[Z]-dienoyl)glycine (5,14-HEDGE), against hypotension, tachycardia, and mortality associated with nitric oxide (NO) mediated-vascular hyporeactivity and inflammation in a model of lipopolysaccharide (LPS)–induced septic shock in rats and mice.…”

“…[1][2][3][4][5] 20-HETE has been implicated in the maintenance of physiological functions of vital organs, including the heart, lung, kidney, and brain, and in the pathogenesis of a wide variety of diseases including hypertension, atherosclerosis, tissue injury, inflammation, sepsis, and septic shock. [6][7][8][9][10][11][12][13] The results of several studies emphasize that 20-HETE has also pro-and antihypertensive effects and pro-and anti-inflammatory properties. 12,[14][15][16][17][18] The heterotrimeric guanine nucleotide-binding proteins (G proteins) serve as transducers of the signal produced by the agonist-receptor complex, thus activating or inhibiting certain signaling downstream pathways via immediate intercommunication with intracellular effector proteins.…”

Unraveling the Role of 12- and 20- HETE in Cardiac Pathophysiology: G-Protein–Coupled Receptors, Pharmacological Inhibitors, and Transgenic Approaches: Erratum

“…In the June 2021 issue of the Journal of Cardiovascular Pharmacology in the article by Pascale et al, “Unraveling the Role of 12- and 20- HETE in Cardiac Pathophysiology: G-Protein–Coupled Receptors, Pharmacological Inhibitors, and Transgenic Approaches,” 1 Figure 1 was incorrect.…”