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Review
. 2011 Nov;96(1-4):45-53.
doi: 10.1016/j.prostaglandins.2011.06.006. Epub 2011 Jun 22.

The role of 20-HETE in androgen-mediated hypertension

Cheng-Chia Wu  1 , Michal Laniado Schwartzman
Affiliations
Review

The role of 20-HETE in androgen-mediated hypertension

Cheng-Chia Wu et al. Prostaglandins Other Lipid Mediat. 2011 Nov.

Abstract

Androgen plays an important role in blood pressure regulation. Epidemiological studies have shown that men have a higher prevalence for developing hypertension than aged-matched, premenopausal women. Interestingly, postmenopausal women and women with polycystic ovary syndrome, both of which have increased endogenous androgen production, have elevated risks for hypertension suggesting that androgen may contribute to its development. Studies from our laboratory and others have provided substantial evidence that 20-hydroxyeicosatetraenoic acid (20-HETE) mediates the hypertension seen in rodents treated with androgen. 20-HETE is the cytochrome P450 (CYP)-derived ω-hydroxylated metabolite of arachidonic acid. 20-HETE plays a complex role in blood pressure regulation. In the kidney tubules, 20-HETE decreases blood pressure by promoting natriuresis, while in the microvasculature it has a pressor effect. In the microcirculation, 20-HETE participates in the regulation of vascular tone by sensitizing the smooth muscle cells to constrictor stimuli and contributes to myogenic, mitogenic and angiogenic responses. In addition, 20-HETE acts on the endothelium to promote endothelial dysfunction and endothelial activation. Recently, we have demonstrated that 20-HETE induces endothelial ACE thus setting forth a potential feed forward mechanism through activation of the renin-angiotensin-aldosterone system. In this review, we will discuss the pro-hypertensive effects of 20-HETE and its role in androgen-induced vascular dysfunction and hypertension.

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Figures

Figure 1
Figure 1. IKK inhibition with parthenolide abrogates 20-HETE-mediated inhibition of acetylcholine-induced relaxations but does not affect 20-HETE-mediated increase in vascular reactivity to phenylephrine
Rat renal interlobar arteries (∼150 μm) were microdissected and placed in a wire myograph. (A) Vascular reactivity to phenylephrine and (B) relaxation to acetylcholine were measured in the presence and absence of parthenolide (5 μg/ml) and 20-HETE (1 μM) as described [33]. Results were analyzed by ANOVA and are mean±SE (n=4); *p<0.05 vs control; #p<0.05 vs 20-HETE alone.
Figure 2
Figure 2. Androgen increases ACE protein levels in a 20-HETE-dependent manner
Rats were treated with DHT (56 mg/kg/day, IP in benzyl alcohol with corn oil) or its vehicle with and without HET0016 (10mg/kg/day) or 20-HEDE (10 mg/kg/day) for 14 days [33]. (A) Renal cortical tissue and (B) microdissected renal interlobar arteries were processed for Western blot analysis of ACE as described [110]. Results were analyzed by ANOVA are mean±SE (n=4); *p<0.05 vs Vehicle; #p<0.05 vs DHT alone.
Figure 3
Figure 3. Androgen receptor blockade with flutamide inhibits androgen-induced hypertension and 20-HETE synthesis
Rats were treated with DHT (56 mg/kg/day, IP in benzyl alcohol with corn oil) or its vehicle with and without Flutamide (50 mg/kg/day, IP in benzyl alcohol with corn oil) for 3 days. (A) Systolic blood pressure and (B) 20-HETE levels in the renal interlobar arteries were measured as described [33]. Results were analyzed by ANOVA are mean±SE (n=4); *p<0.05 vs vehicle control; #p<0.05 vs DHT alone.
Figure 4
Figure 4. Postulated vascular mechanisms underlying the pro-hypertensive actions of 20-HETE
In most vascular beds, the synthesis of 20-HETE is primarily localized to the vascular smooth muscle where it is subjected to regulation by various autacoids [125] as well as androgen. In the vascular smooth muscle, 20-HETE elicits vasoconstriction largely via inhibition of the SMC large-conductance Ca2+-activated K+ channel, leading to depolarization and elevation in cytosolic [Ca2+] [54], and in some blood vessels via a Rho-kinase phosphorylation of MLC20 and the sensitization of the contractile apparatus to Ca2+ [61]. 20-HETE acts on the endothelium in a paracrine manner through a yet to be identified “receptor”; it stimulates IKK activation through EGFR and MAPK (ERK1/2). The activation of IKK is a key signaling mechanism of 20-HETE actions in the vascular endothelium as it leads to eNOS uncoupling, NF-kB activation and ACE induction [73, 74]. The induction of ACE by 20-HETE brings about increases in Ang II levels and its actions through the AT1R in vascular smooth muscle and endothelial cells, thus setting up a feed forward amplification of 20-HETE-induced vascular dysfunction by the RAS. Vasoconstriction, endothelial dysfunction and endothelial activation are all contributing to hypertension.
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