20-Hydroxyeicosatetraenoic Acid (20-HETE) Is a Novel Activator of Transient Receptor Potential Vanilloid 1 (TRPV1) Channel

Wen, Hairuo; Östman, Johan; Bubb, Kristen J.; Panayiotou, Catherine M; Priestley, John V.; Baker, Mark D.; Ahluwalia, Amrita

doi:10.1074/jbc.m111.334896

Cited by 67 publications

(57 citation statements)

References 32 publications

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“…As TRPV1 phosphorylation and hence activity are enhanced by inflammatory mediators, we investigated whether such mediators (ie, PGE 2 via a cAMP-PKA signaling-dependent pathway) 17,21 might also sensitize arteries to TRPV1-mediated constriction. Indeed, PGE 2 enhanced pressure-induced constriction of arteries of male WT mice ( Figure 5A; P=0.0129) but not male TRPV1 KO ( Figure 5B) or female WT mice ( Figure 5C).…”

Section: Enhanced Trpv1 Activity Underlies Enhanced Vasoconstrictionmentioning

confidence: 99%

“…This observation mirrors our recent observations measuring channel activity in isolated DRG neurons and TRPV1-transfected human embryonic kidney cells. 17 This is also a characteristic of other TRPV1 activators, including the satiety factor oleoylethanolamide 37 and even more recently capsaicin itself. 38 We also show that sensitization of TRPV1 with the inflammogen and PKA activator PGE 2 , or 20-HETE itself, results in heightened TRPV1-mediated vasoconstriction as evidenced by increased constriction of blood vessels to elevations in intraluminal pressure.…”

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confidence: 96%

“…16 More recently, we have demonstrated that 20-HETE, which is structurally closely related to 12-hydroperoxyeicosatetraenoic acid, is also an activator of neuronal TRPV1 and sensitizes the channel to other stimulators in a protein kinase A (PKA)-dependent manner. 17 Importantly, sensitization of TRPV1 consequent to phosphorylation has been implicated as a key proinflammatory pathway activated in inflammatory models of disease. 18 Thus, we hypothesize that 20-HETE-induced activation of TRPV1 might underlie its vasoconstrictor and hypertensive activity.…”

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confidence: 99%

“…First, there is substantial evidence that PGE 2 is a potent sensitizer of TRPV1 via stimulation of phosphorylation of specific residues. 17,19 Furthermore, PGE 2 has been implicated as a key inflammogen involved in the pathogenesis of a range of cardiovascular disorders, not least in hypertension and vascular injury. 39,40 Further studies exploring the role of PGE 2 and the TRPV1 pathway in vivo are warranted.…”

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confidence: 99%

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Activation of Neuronal Transient Receptor Potential Vanilloid 1 Channel Underlies 20-Hydroxyeicosatetraenoic Acid–Induced Vasoactivity

et al. 2013

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Abstract-A rise in intraluminal pressure triggers vasoconstriction in resistance arteries, which is associated with local generation of the vasoconstrictor 20-hydroxyeicosatetraenoic acid (20-HETE). Importantly, dysregulation of 20-HETE synthesis and activity has been implicated in several cardiovascular disease states, including ischemic disease, hypertension, and stroke; however, the exact molecular pathways involved in mediating 20-HETE bioactivity are uncertain. We investigated whether 20-HETE activates the transient receptor potential vanilloid 1 (TRPV1) and thereby regulates vascular function and blood pressure. We demonstrate that 20-HETE causes dose-dependent increases in blood pressure, coronary perfusion pressure (isolated Langendorff), and pressure-induced constriction of resistance arteries (perfusion myography) that is substantially attenuated in TRPV1 knockout mice and by treatment with the neurokinin 1 receptor antagonist RP67580. Furthermore, we show that both channel activation (via patch-clamping of dorsal root ganglion neurons) and vessel constriction are enhanced under inflammatory conditions, and our findings indicate a predominant role for protein kinase A-mediated sensitization of TRPV1 in these phenomena. Finally, we identify a prominence of these pathway in males compared with females, an effect we relate to reduced protein kinase A-induced phosphorylation of TRPV1. 20-HETE-induced activation of TRPV1, in part, mediates pressure-induced myogenic constriction and underlies 20-HETE-induced elevations in blood pressure and coronary resistance.

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Section: Enhanced Trpv1 Activity Underlies Enhanced Vasoconstrictionmentioning

confidence: 99%

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confidence: 96%

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Activation of Neuronal Transient Receptor Potential Vanilloid 1 Channel Underlies 20-Hydroxyeicosatetraenoic Acid–Induced Vasoactivity

et al. 2013

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“…In the vasculature 20-HETE has direct effects on endothelial and vascular smooth muscle reactivity, but also counteracts natriuresis in the kidney (4, 13). 20-HETE also activates transient receptor potential cation channel, subfamily V, member 1 (TRPV1) to promote myogenic constriction (1,23). Regardless of the ultimate effector, in the study by Dordea et al (5a), the 20-HETE antagonist 20-HEDE had little or no effect on blood pressure in wild-type animals, suggesting that under basal conditions, NO-sGC signaling completely suppresses the activity of 20-HETE from a physiological standpoint.…”

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Guanylyl cyclase can't stand the HETE

Hobbs

2016

American Journal of Physiology-Heart and Circulatory Physiology

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NITRIC OXIDE (NO)-sensitive isoforms of heterodimeric guanylyl cyclase [␣ 1 ␤ 1 -and ␣ 2 ␤ 1 -soluble guanylyl cyclases (sGC)], extend an umbrella of protection throughout the cardiovascular system, with wide-ranging effects on local blood flow, platelet and leukocyte reactivity, vessel morphology, and cardiac structure and function (5, 10). Consequently, dysfunctional sGC signaling precipitates cardiovascular disease in an analogous manner to deficits in NO bioactivity, perhaps illustrated most tangibly in the context of human pathophysiology by genomewide association studies (GWAS) identifying mutations in the GUCY1A3 and GUCY1B3 genes, which encode the two principal subunits of the enzyme (sGC␣ 1 and sGC␤ 1 , respectively), to associate with a hypertensive phenotype (6). Preclinical models have also borne out a clear relationship between sGC activity, local vascular tone, and systemic blood pressure. This is best illustrated by the hypertensive phenotype in mice with genetic deletions of either sGC␣ 1 or sGC␤ 1 (3,8,9,17,19). Interestingly, the sGC␣ 1 and sGC␤ 1 null mice exhibit a strainand sex-specific rise in blood pressure (3,17), and this phenomenon has shed light on mechanisms critical to the vasoprotective functions of NO-sGC signaling, both in terms of endothelium-dependent dilatation and more global effects on neurohormonal axes. For example, the sex difference in response to sGC deletion dovetails well with studies revealing a marked increase in blood pressure in male endothelial NO synthase (eNOS)/cyclooxygenase-1 double knockout (KO) mice, which are unable to synthesize two principal endotheliumderived vasodilators, NO and prostacyclin (14). In these animals, endothelium-dependent relaxation is restricted to that provided by hyperpolarization pathways, i.e., endotheliumdependent hyperpolarization (EDH), which are upregulated by female sex steroids (20); in contrast, the predominant endothelium-derived dilator in males is NO, thereby explaining why deletion of eNOS or sGC results in raised blood pressure. Consequently, sGC KO mice are good models with which to ascertain the role of male sex steroids, primarily testosterone, in the development of hypertension. For example, previous studies capitalizing on the sGC␣ 1 KO mice have revealed an androgen-driven increase in renin activity that contributes to the hypertensive phenotype in these animals (2, 3).In this issue of the American Journal of Physiology-Heart and Circulatory Physiology, Dordea et al. (5a) provide a timely and thought-provoking report identifying a further pathway upregulated by sGC␣ 1 deletion that underlies the development of hypertension in a sex-specific manner. Via linkage analysis, the authors identified a quantitative trait locus that associates with elevated blood pressure in male 129S6 mice that is shared by neither counterparts on a C57BL6 background nor female animals of either strain. In-depth analysis revealed that this region encodes a cluster of the cytochrome P-450 (Cyp) 4a isoforms, including Cyp4a10, Cyp4a12, and Cy...

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Nonenzymatically oxidized arachidonic acid regulates T‐type Ca²⁺ currents in mouse spermatogenic cells

et al. 2019

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During spermatogenesis, fatty acids play an important role both as structural components and messengers that trigger male germ cell line differentiation. The spontaneous oxidation of fatty acids causes a decrease in mammalian fertility. Here, we examine the effects of nonenzymatically oxidized arachidonic acid (AAox) on mouse spermatogenic T‐type Ca2+ currents (ICaT) due to their physiological relevance during spermatogenesis. AAox is 25‐fold more potent than AA at inhibiting ICaT and it left shifts the I‐V curve peak and both activation and steady‐state inactivation curves. In addition, ICaT deactivation kinetics and their recovery from inactivation are slower in the presence of AAox. Therefore, the fraction of inactivated Ca2+ channels is increased. AAox‐induced ICaT inhibition could contribute to male infertility affecting Ca2+ regulation in spermatogenic cells.

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20-Hydroxyeicosatetraenoic Acid (20-HETE) Is a Novel Activator of Transient Receptor Potential Vanilloid 1 (TRPV1) Channel

Cited by 67 publications

References 32 publications

Activation of Neuronal Transient Receptor Potential Vanilloid 1 Channel Underlies 20-Hydroxyeicosatetraenoic Acid–Induced Vasoactivity

Activation of Neuronal Transient Receptor Potential Vanilloid 1 Channel Underlies 20-Hydroxyeicosatetraenoic Acid–Induced Vasoactivity

Guanylyl cyclase can't stand the HETE

Nonenzymatically oxidized arachidonic acid regulates T‐type Ca²⁺ currents in mouse spermatogenic cells

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20-Hydroxyeicosatetraenoic Acid (20-HETE) Is a Novel Activator of Transient Receptor Potential Vanilloid 1 (TRPV1) Channel

Cited by 67 publications

References 32 publications

Activation of Neuronal Transient Receptor Potential Vanilloid 1 Channel Underlies 20-Hydroxyeicosatetraenoic Acid–Induced Vasoactivity

Activation of Neuronal Transient Receptor Potential Vanilloid 1 Channel Underlies 20-Hydroxyeicosatetraenoic Acid–Induced Vasoactivity

Guanylyl cyclase can't stand the HETE

Nonenzymatically oxidized arachidonic acid regulates T‐type Ca2+ currents in mouse spermatogenic cells

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Product

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Nonenzymatically oxidized arachidonic acid regulates T‐type Ca²⁺ currents in mouse spermatogenic cells