Estrogen Metabolite 2-methoxyestradiol Prevents Hypertension in Deoxycorticosterone Acetate-salt Rats

Yuan, Wensu; Yu, Yueyi; Li, Jingjing; Singh, Pavneet; Dong, Lixue; Gui, Yu; Zheng, Xi-Long

doi:10.1007/s10557-012-6428-7

Cited by 13 publications

(8 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Since Cyp1b1 gene disruption and treatment with TMS or OVX in Cyp1b1 +/+ mice and 2-OHE or 2-MeE2 in Cyp1b1 +/+ or Cyp1b1 −/− mice did not alter basal SBP, it appears that 2-MeE2 modulates Ang II-induced hypertension by acting as a permissive factor. 2-MeE2 also minimizes hypertension and associated coronary vascular remodeling in male and OVX spontaneously hypertensive rats (39) and prevents DOCA-salt-induced hypertension in male rats (40). …”

Section: Discussionmentioning

confidence: 99%

Estrogen Metabolism by Cytochrome P450 1B1 Modulates the Hypertensive Effect of Angiotensin II in Female Mice

et al. 2014

View full text Add to dashboard Cite

To determine the role of CYP1B1 in the gender difference in response to Ang II-induced hypertension, female Cyp1b1+/+ and Cyp1b1−/− mice were infused with Ang II (700 ng/kg/min) or vehicle with/without ovariectomy. In addition, mice were treated with the CYP1B1 inhibitor, 2,3′,4,5′-tetramethoxystilbene (TMS, 300 μg/kg, every 3rd day, i.p.), and 17-β-estradiol metabolites, 2-hydroxyestradiol (2-OHE), 4-OHE, or 2-methoxyestradiol (2-MeE2) (1.5 mg/kg/day, i.p., for 2 weeks), and systolic blood pressure (SBP) measured. Ang II increased SBP more in Cyp1b1−/− than in Cyp1b1+/+ mice (119±3 to 171±11 mmHg vs. 120±4 to 149±4 mmHg, P<0.05). Ang II caused cardiovascular remodeling and endothelial dysfunction, and increased vascular reactivity and oxidative stress in Cyp1b1−/− but not Cyp1b1+/+mice. The Ang II-induced increase in SBP was enhanced by ovariectomy and TMS in Cyp1b1+/+ but not Cyp1b1−/− mice. 2-OHE did not alter Ang II-induced increase in SBP in Cyp1b1+/+ mice but minimized it in Cyp1b1−/− mice, whereas 4-OHE enhanced Ang II-induced increase in SBP in Cyp1b1+/+ mice but did not alter the increased SBP in Cyp1b1−/− mice. 2-OHE-derived catechol-O-methyltransferase metabolite, 2-MeE2, inhibited Ang II-induced increase in SBP in Cyp1b1−/− mice. Ang II increased plasma levels of 2MeE2 in Cyp1b1+/+ but not Cyp1b1−/− mice, and increased activity of cardiac extracellular signal-regulated kinase 1/2, p38 mitogen-activated kinase, c-Src, and Akt in Cyp1b1−/− but not Cyp1b1+/+ mice. These data suggest that CYP1B1 protects against Ang II-induced hypertension and associated cardiovascular changes in female mice, most likely mediated by 2-MeE2-inhibiting oxidative stress and the activity of these signaling molecules.

show abstract

Section: Discussionmentioning

confidence: 99%

Estrogen Metabolism by Cytochrome P450 1B1 Modulates the Hypertensive Effect of Angiotensin II in Female Mice

et al. 2014

View full text Add to dashboard Cite

show abstract

“…15,16 Peripheral administration of estradiol rescued male rats from deoxycorticosterone acetate-salt and Ang II-induced hypertension. 21 Moreover, 2-ME also prevented deoxycorticosterone acetate-salt-induced hypertension in male rats, 22 and attenuated hypertension, coronary vascular remodeling and ischemia reperfusion injury in mice. 23,24 …”

Section: Discussionmentioning

confidence: 94%

2-Methoxyestradiol Reduces Angiotensin II–Induced Hypertension and Renal Dysfunction in Ovariectomized Female and Intact Male Mice

et al. 2017

View full text Add to dashboard Cite

cytochrome P45 1B1 protects against angiotensin II-induced hypertension and associated cardiovascular changes in female mice, most likely via production of 2-methoxyestradiol. This study was conducted to determine if 2-methoxyestradiol ameliorates angiotensin II-induced hypertension, renal dysfunction, and end-organ damage in intact Cyp1b1−/−, ovariectomized female, and in Cyp1b1+/+ male mice. Ang II or vehicle was infused for 2 weeks and administered concurrently with 2-methoxyestradiol. Mice were placed in metabolic cages on day 12 of Ang II infusion for urine collection for 24 h. 2-Methoxyestradiol reduced angiotensin II-induced increases in systolic blood pressure, water consumption, urine output, and proteinuria in intact female Cyp1b1−/− and ovariectomized mice. 2-Methoxyestradiol also reduced Ang II-induced increase in blood pressure, water intake, urine output, and proteinuria in Cyp1b1+/+ male mice. Treatment with 2-methoxyestradiol attenuated Ang II-induced end-organ damage in intact Cyp1b1−/− and ovariectomized Cyp1b1+/+ and Cyp1b1−/− female mice, and Cyp1b1+/+ male mice. 2-Methoxyestradiol mitigated Ang II-induced increase in urinary excretion of angiotensinogen in intact Cyp1b1−/− and ovariectomized Cyp1b1+/+ and Cyp1b1−/− female mice but not in Cyp1b1+/+ male mice. The G-protein-coupled estrogen receptor 1 antagonist G-15 failed to alter Ang II-induced increases in blood pressure and renal function in Cyp1b1+/+ female mice. These data suggest that 2-methoxyestradiol reduces angiotensin II-induced hypertension and associated end-organ damage in intact Cyp1b1−/−, ovariectomized Cyp1b1+/+ and Cyp1b1−/− female mice, and Cyp1b1+/+ male mice independent of G protein-coupled estrogen receptor 1. Therefore, 2-methoxyestradiol could serve as a therapeutic agent for treating hypertension and associated pathogenesis in postmenopausal females, and in males.

show abstract

“…As 2ME2 was reported to modulate vascular contractility and blood pressure (Tofovic et al 2005;Yuan et al 2013), physiological parameters including NIBP, peripheral oxygen saturation, heart rate, as well as neurological severity score and motor coordination were monitored. However, no significant differences were observed between sham and TBI mice that received vehicle or high-dose 2ME2 (Table S1).…”

Section: Me2 Attenuates Secondary Brain Damage In Experimental Tbimentioning

confidence: 99%

2‐Methoxyestradiol confers neuroprotection and inhibits a maladaptive HIF‐1α response after traumatic brain injury in mice

Schaible

Windschügl

Bobkiewicz

et al. 2014

Journal of Neurochemistry

View full text Add to dashboard Cite

HIF-1a is pivotal for cellular homeostasis in response to cerebral ischemia. Pharmacological inhibition of HIF-1a may reduce secondary brain damage by targeting post-translational mechanisms associated with its proteasomal degradation and nuclear translocation. This study examined the neuroprotective effects of 2-methoxyestradiol (2ME2), the involved HIF-1a-dependent response, and alternative splicing in exon 14 of HIF-1a (HIF-1aΔEx14) after traumatic brain injury (TBI) in mice. Intraperitoneal 2ME2 administration 30 min after TBI caused a dose-dependent reduction in secondary brain damage after 24 h. 2ME2 was physiologically tolerated, showed no effects on immune cell brain migration, and mitigated trauma-induced brain expression of neuropathologically relevant HIF-1a target genes encoding for Plasminogen activator inhibitor 1 and tumor necrosis factor alpha. Moreover, TBI-induced expression of pro-apoptotic BNIP3 was attenuated by 2ME2 treatment. Alternatively, spliced HIF-1aΔEx14 was substantially up-regulated from 6 to 48 h after TBI. In vitro, nuclear location and gene transcription activity of HIF-1aΔEx14 were impaired compared to full-length HIF-1a, but no effects on nuclear translocation of the transcriptional complex partner HIF-1b were observed. This study demonstrates that 2ME2 confers neuroprotection after TBI. While the role of alternatively spliced HIF-1aΔEx14 remains elusive, the in vivo data provide evidence that inhibition of a maladaptive HIF-1a-dependent response contributes to the neuroprotective effects of 2ME2. Keywords: 2-methoxyestradiol, alternative splicing, cerebral ischemia, HIF-1, neuroprotection, traumatic brain injury.

show abstract

Estrogen Metabolite 2-methoxyestradiol Prevents Hypertension in Deoxycorticosterone Acetate-salt Rats

Abstract: 2ME treatment prevents the development of hypertension in DOCA-salt rats, implicating a therapeutic potential of 2ME in hypertension treatment.

Cited by 13 publications

References 20 publications

Estrogen Metabolism by Cytochrome P450 1B1 Modulates the Hypertensive Effect of Angiotensin II in Female Mice

Estrogen Metabolism by Cytochrome P450 1B1 Modulates the Hypertensive Effect of Angiotensin II in Female Mice

2-Methoxyestradiol Reduces Angiotensin II–Induced Hypertension and Renal Dysfunction in Ovariectomized Female and Intact Male Mice

2‐Methoxyestradiol confers neuroprotection and inhibits a maladaptive HIF‐1α response after traumatic brain injury in mice

Contact Info

Product

Resources

About