20-Hydroxyeicosatetraenoic Acid (HETE)-dependent Hypertension in Human Cytochrome P450 (CYP) 4A11 Transgenic Mice

Savas, Üzen; Wei, Shouzou; Hsu, Mei Hui; Falck, John R.; Guengerich, F. Peter; Capdevila, Jorge H.; Johnson, Eric F.

doi:10.1074/jbc.m116.732297

Cited by 27 publications

(13 citation statements)

References 69 publications

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“…52 Interestingly, salt-sensitive hypertension in mice expressing the human CYP4A11-20-HETE synthase was attributed to enhanced Na retention resulting from 20-HETE- and Ang II-dependent NCC upregulation. 53 Salt-sensitive hypertension was also shown in rats with depressed renal medullary 20-HETE synthesis, which conditions Na retention in the ascending limb of the loop of Henle. 54–57 Inasmuch as 20-HETE contributes to pro-hypertensive mechanisms via vascular and tubular actions that foster vasoconstriction and/or conservation of sodium, and to anti-hypertensive mechanisms via actions that facilitate Na excretion, it is expected that the blood pressure effect of interventions that interfere with 20-HETE actions is conditioned by both mechanisms.…”

Section: Discussionmentioning

confidence: 99%

20-HETE Signals Through G-Protein–Coupled Receptor GPR75 (G _q ) to Affect Vascular Function and Trigger Hypertension

García

Gilani

Shkolnik

et al. 2017

Circulation Research

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134

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Rationale 20-Hydroxyeicosatetraenoic acid (20-HETE), one of the principle cytochrome P450 (CYP) eicosanoids, is a potent vasoactive lipid whose vascular effects include stimulation of smooth muscle contractility, migration and proliferation, as well as endothelial cell dysfunction and inflammation. Increased levels of 20-HETE in experimental animals and in humans are associated with hypertension, stroke, myocardial infarction and vascular diseases. Objective To date, a receptor/binding site for 20-HETE has been implicated based on the use of specific agonists and antagonists. The present study was undertaken to identify a receptor to which 20-HETE binds and through which it activates a signaling cascade that culminates in many of the functional outcomes attributed to 20-HETE in vitro and in vivo. Methods and Results Using crosslinking analogs, click chemistry, binding assays, and functional assays, we identified GPR75, currently an orphan G-protein coupled receptor (GPCR), as a specific target of 20-HETE. In cultured human endothelial cells, 20-HETE binding to GPR75 stimulated Gαq/11 protein dissociation and increased inositol phosphate (IP-1) accumulation as well as GPCR-kinase interacting protein-1 (GIT1)-GPR75 binding, which further facilitated the c-Src-mediated transactivation of endothelial EGFR. This results in downstream signaling pathways which induce angiotensin-converting enzyme (ACE) expression and endothelial dysfunction. Knockdown of GPR75 or GIT1 prevented 20-HETE-mediated endothelial growth factor receptor (EGFR) phosphorylation and ACE induction. In vascular smooth muscle cells, GPR75-20-HETE pairing is associated with Gαq/11- and GIT1-mediated protein kinase C (PKC)-stimulated phosphorylation of MaxiKβ, λinking GPR75 activation to 20-HETE-mediated vasoconstriction. GPR75 knockdown in a mouse model of 20-HETE-dependent hypertension prevented blood pressure elevation and 20-HETE-mediated increases in ACE expression, endothelial dysfunction, smooth muscle contractility and vascular remodeling. Conclusions This is the first report to identify a GPCR target for an eicosanoid of this class. The discovery of 20-HETE-GPR75 pairing presented here provides the molecular basis for the signaling and pathophysiological functions mediated by 20-HETE in hypertension and cardiovascular diseases.

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Section: Discussionmentioning

confidence: 99%

20-HETE Signals Through G-Protein–Coupled Receptor GPR75 (G _q ) to Affect Vascular Function and Trigger Hypertension

García

Gilani

Shkolnik

et al. 2017

Circulation Research

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134

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“…Volume Pressure Recording (VPR) sensor technology for tail‐cuff, presently one of the most widely used, was validated by Feng et al 10. It is commonly cited that they found negligible difference between telemetry and the VPR systems,25, 26 despite an apparent difference in individual recordings or lack of consistent results across the whole range of blood pressure recordings.…”

Section: Introductionmentioning

confidence: 99%

Tail‐Cuff Technique and Its Influence on Central Blood Pressure in the Mouse

Wilde

Aubdool

Thakore

et al. 2017

JAHA

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BackgroundReliable measurement of blood pressure in conscious mice is essential in cardiovascular research. Telemetry, the “gold‐standard” technique, is invasive and expensive and therefore tail‐cuff, a noninvasive alternative, is widely used. However, tail‐cuff requires handling and restraint during measurement, which may cause stress affecting blood pressure and undermining reliability of the results.Methods and ResultsC57Bl/6J mice were implanted with radio‐telemetry probes to investigate the effects of the steps of the tail‐cuff technique on central blood pressure, heart rate, and temperature. This included comparison of handling techniques, operator's sex, habituation, and influence of hypertension induced by angiotensin II. Direct comparison of measurements obtained by telemetry and tail‐cuff were made in the same mouse. The results revealed significant increases in central blood pressure, heart rate, and core body temperature from baseline following handling interventions without significant difference among the different handling technique, habituation, or sex of the investigator. Restraint induced the largest and sustained increase in cardiovascular parameters and temperature. The tail‐cuff readings significantly underestimated those from simultaneous telemetry recordings; however, “nonsimultaneous” telemetry, obtained in undisturbed mice, were similar to tail‐cuff readings obtained in undisturbed mice on the same day.ConclusionsThis study reveals that the tail‐cuff technique underestimates the core blood pressure changes that occur simultaneously during the restraint and measurement phases. However, the measurements between the 2 techniques are similar when tail‐cuff readings are compared with telemetry readings in the nondisturbed mice. The differences between the simultaneous recordings by the 2 techniques should be recognized by researchers.

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“…This observation supports the notion that there is a close interaction between 20-HETE and RAS activity. Besides evidence of positive feedback interactions, 20-HETE seems to contribute directly to ANG II vasoconstriction, vascular remodeling, and inflammatory processes [ 19 , 27 , 57 , 60 ]. Therefore the organoprotection effect of the 20-HETE antagonist treatment observed also in the present study might be predominantly attributed to lowering of ANG II concentration accompanied by significant reduction in SBP in this model.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, it has been documented that functional interaction between RAS and 20-HETE at the vascular level is complex and both components work in concert to promote the development of hypertension [ 21–26 ]. Moreover, recent studies suggested that 20-HETE might represent an upstream effector molecule for the activation of RAS in the vasculature [ 23 , 27–29 ].…”

Section: Introductionmentioning

confidence: 99%

20-Hydroxyeicosatetraenoic acid antagonist attenuates the development of malignant hypertension and reverses it once established: a study in Cyp1a1-Ren-2 transgenic rats

et al. 2018

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We hypothesized that vascular actions of 20-hydroxyeicosatetraenoic acid (20-HETE), the product of cytochrome P450 (CYP450)-dependent ω-hydroxylase, potentiate prohypertensive actions of angiotensin II (ANG II) in Cyp1a1-Ren-2 transgenic rats, a model of ANG II-dependent malignant hypertension. Therefore, we evaluated the antihypertensive effectiveness of 20-HETE receptor antagonist (AAA) in this model. Malignant hypertension was induced in Cyp1a1-Ren-2 transgenic rats by activation of the renin gene using indole-3-carbinol (I3C), a natural xenobiotic. Treatment with AAA was started either simultaneously with induction of hypertension or 10 days later, during established hypertension. Systolic blood pressure (SBP) was monitored by radiotelemetry, indices of renal and cardiac injury, and kidney ANG II levels were determined. In I3C-induced hypertensive rats, early AAA treatment reduced SBP elevation (to 161 ± 3 compared with 199 ± 3 mmHg in untreated I3C-induced rats), reduced albuminuria, glomerulosclerosis index, and cardiac hypertrophy (P<0.05 in all cases). Untreated I3C-induced rats showed augmented kidney ANG II (405 ± 14 compared with 52 ± 3 fmol/g in non-induced rats, P<0.05) which was markedly lowered by AAA treatment (72 ± 6 fmol/g). Remarkably, in TGR with established hypertension, AAA also decreased SBP (from 187 ± 4 to 158 ± 4 mmHg, P<0.05) and exhibited organoprotective effects in addition to marked suppression of kidney ANG II levels. In conclusion, 20-HETE antagonist attenuated the development and largely reversed the established ANG II-dependent malignant hypertension, likely via suppression of intrarenal ANG II levels. This suggests that intrarenal ANG II activation by 20-HETE is important in the pathophysiology of this hypertension form.

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20-Hydroxyeicosatetraenoic Acid (HETE)-dependent Hypertension in Human Cytochrome P450 (CYP) 4A11 Transgenic Mice

Cited by 27 publications

References 69 publications

20-HETE Signals Through G-Protein–Coupled Receptor GPR75 (G _q ) to Affect Vascular Function and Trigger Hypertension

20-HETE Signals Through G-Protein–Coupled Receptor GPR75 (G _q ) to Affect Vascular Function and Trigger Hypertension

Tail‐Cuff Technique and Its Influence on Central Blood Pressure in the Mouse

20-Hydroxyeicosatetraenoic acid antagonist attenuates the development of malignant hypertension and reverses it once established: a study in Cyp1a1-Ren-2 transgenic rats

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20-Hydroxyeicosatetraenoic Acid (HETE)-dependent Hypertension in Human Cytochrome P450 (CYP) 4A11 Transgenic Mice

Cited by 27 publications

References 69 publications

20-HETE Signals Through G-Protein–Coupled Receptor GPR75 (G q ) to Affect Vascular Function and Trigger Hypertension

20-HETE Signals Through G-Protein–Coupled Receptor GPR75 (G q ) to Affect Vascular Function and Trigger Hypertension

Tail‐Cuff Technique and Its Influence on Central Blood Pressure in the Mouse

20-Hydroxyeicosatetraenoic acid antagonist attenuates the development of malignant hypertension and reverses it once established: a study in Cyp1a1-Ren-2 transgenic rats

Contact Info

Product

Resources

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20-HETE Signals Through G-Protein–Coupled Receptor GPR75 (G _q ) to Affect Vascular Function and Trigger Hypertension

20-HETE Signals Through G-Protein–Coupled Receptor GPR75 (G _q ) to Affect Vascular Function and Trigger Hypertension