Abstract P2029: Cytochrome P450 (CYP) 1B1-Estradiol Metabolite 2-Methoxyestradiol Protects Against Angiotensin II-induced Hypertension By Inhibiting CYP4A1 Expression 20-Hydroxyeicosatetraenoic Acid (20-HETE) Production In The Female Mice

Hypertension ◽  
2019 ◽  
Vol 74 (Suppl_1) ◽  
Author(s):  
Chi Young Song ◽  
Ji Soo Shin ◽  
Jessica Lew ◽  
John Falck ◽  
Kafait Malik
Keyword(s):  
Cytochrome P450 ◽  
Angiotensin Ii ◽  
Hydroxyeicosatetraenoic Acid ◽  
Female Mice ◽  
Induced Hypertension

Abstract P135: 2-methoxyestradiol Minimizes Angiotensin II-induced Hypertension and Renal Dysfunction in Ovariectomized Female and Intact Male Mice

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Ajeeth K Pingili ◽  
Shyamala Thirunavukkarasu ◽  
Nayaab S Khan ◽  
Akemi Katsurada ◽  
Dewan S Majid ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Renal Dysfunction ◽  
Organ Damage ◽  
Ang Ii ◽  
Male Mice ◽  
Intact Male ◽  
Female Mice ◽  
End Organ Damage ◽  
Induced Hypertension ◽  
Post Menopausal

Men and post-menopausal females are more prone to develop hypertension and renal dysfunction as compared to pre-menopausal females. It is well documented that in various experimental models of hypertension, the protection against hypertension in females is lost following ovariectomy (OVX). Recently we have shown that CYP1B1 protects against angiotensin II (Ang II)-induced hypertension and associated cardiovascular changes in female mice, most likely via production of 2-methoxyestradiol (2-ME). This study was conducted to determine if 2-ME reduces Ang II-induced hypertension, renal dysfunction and end organ damage in OVX female, and intact male mice. Treatment of OVX Cyp1b1 +/+ and Cyp1b1 -/- female mice with 2-ME (1.5 mg/kg/day i.p., for 2 weeks) reduced Ang II-induced increase in systolic blood pressure (SBP) (182±5.1 vs. 143± 2.4 mmHg, 179±6.4 vs. 140± 8.6 mmHg, P < 0.05, n= 5), water consumption, urine output and osmolality, and proteinuria (5.5±0.7 vs. 3.3±0.5 mg/24 hrs, 8.4±1.3 vs. 4.4 ±0.9 mg/24 hrs) respectively. 2-ME also reduced Ang II-induced increase in SBP (188±2.6 vs. 143± 2.7 mmHg, P < 0.05, n= 5) in intact male mice. 2-ME did not alter water consumption and urine osmolality, but reduced urine output and sodium excretion, and proteinuria (14.4±2.0 vs. 6.0±0.5 mg/24 hrs) in intact Cyp1b1 +/+ male mice. Treatment with 2-ME attenuated Ang II-induced end-organ damage (actin and collagen accumulation) in OVX Cyp1b1 +/+ and Cyp1b1 -/- female and Cyp1b1 +/+ male mice. 2-ME mitigated urinary excretion of angiotensinogen in OVX Cyp1b1 +/+ and Cyp1b1 -/- female mice infused with Ang II. These data suggest that 2-ME reduces Ang II- induced hypertension and associated renal dysfunction and end-organ damage in OVX Cyp1b1 +/+ and Cyp1b1 -/- female, and intact male mice. Therefore, 2-ME could serve as a therapeutic agent for treatment of hypertension and associated pathogenesis in post-menopausal females, and intact males.

Estrogen receptor-α mediates estrogen protection from angiotensin II-induced hypertension in conscious female mice

2007 ◽  
Vol 292 (4) ◽  
pp. H1770-H1776 ◽  
Author(s):  
Baojian Xue ◽  
Jaya Pamidimukkala ◽  
Dennis B. Lubahn ◽  
Meredith Hay
Keyword(s):  
Estrogen Receptor ◽  
Angiotensin Ii ◽  
Estrogen Receptor Α ◽  
Protective Role ◽  
Protective Effects ◽  
Pressor Effect ◽  
Ang Ii ◽  
Female Mice ◽  
Female Sex Hormones ◽  
Induced Hypertension

It has been shown that the female sex hormones have a protective role in the development of angiotensin II (ANG II)-induced hypertension. The present study tested the hypotheses that 1) the estrogen receptor-α (ERα) is involved in the protective effects of estrogen against ANG II-induced hypertension and 2) central ERs are involved. Blood pressure (BP) was measured in female mice with the use of telemetry implants. ANG II (800 ng·kg−1·min−1) was administered subcutaneously via an osmotic pump. Baseline BP in the intact, ovariectomized (OVX) wild-type (WT) and ERα knockout (ERαKO) mice was similar; however, the increase in BP induced by ANG II was greater in OVX WT (23.0 ± 1.0 mmHg) and ERαKO mice (23.8 ± 2.5 mmHg) than in intact WT mice (10.1 ± 4.5 mmHg). In OVX WT mice, central infusion of 17β-estradiol (E2; 30 μg·kg−1·day−1) attenuated the pressor effect of ANG II (7.0 ± 0.4 mmHg), and this protective effect of E2 was prevented by coadministration of ICI-182,780 (ICI; 1.5 μg·kg−1·day−1, 18.8 ± 1.5 mmHg), a nonselective ER antagonist. Furthermore, central, but not peripheral, infusions of ICI augmented the pressor effects of ANG II in intact WT mice (17.8 ± 4.2 mmHg). In contrast, the pressor effect of ANG II was unchanged in either central E2-treated OVX ERαKO mice (19.0 ± 1.1 mmHg) or central ICI-treated intact ERαKO mice (19.6 ± 1.6 mmHg). Lastly, ganglionic blockade on day 7 after ANG II infusions resulted in a greater reduction in BP in OVX WT, central ER antagonist-treated intact WT, central E2 + ICI-treated OVX WT, ERαKO, and central E2- or ICI-treated ERαKO mice compared with that in intact WT mice given just ANG II. Together, these data indicate that ERα, especially central expression of the ER, mediates the protective effects of estrogen against ANG II-induced hypertension.

scholarly journals 6β-Hydroxytestosterone, a Cytochrome P450 1B1 Metabolite of Testosterone, Contributes to Angiotensin II–Induced Hypertension and Its Pathogenesis in Male Mice

Hypertension ◽  
2015 ◽  
Vol 65 (6) ◽  
pp. 1279-1287 ◽  
Author(s):  
Ajeeth K. Pingili ◽  
Mehmet Kara ◽  
Nayaab S. Khan ◽  
Anne M. Estes ◽  
Zongtao Lin ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Angiotensin Ii ◽  
Male Mice ◽  
Cytochrome P450 1B1 ◽  
Induced Hypertension

Abstract P012: Cytochrome P450 1B1 Generated 17β-Estradiol Metabolite 2-Methoxyestradiol Inhibits 12/15-Lipoxygenase To Protect Against Angiotensin II-induced Hypertension, Autonomic Dysfunction And Renal Injury In Female Mice

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Purnima Singh ◽  
Shubha Ranjan Dutta ◽  
Kafait U Malik
Keyword(s):  
Cytochrome P450 ◽  
Renal Injury ◽  
Power Spectral Analysis ◽  
High Frequency Oscillation ◽  
Ang Ii ◽  
Creatinine Ratio ◽  
Albumin Creatinine Ratio ◽  
Female Mice ◽  
Induced Hypertension ◽  
17Β Estradiol

17β-estradiol (E2) via its cytochrome P450 (CYP) 1B1 generated metabolite 2-methoxyestradiol (2ME) protects from angiotensin (Ang) II-induced hypertension in female mice. Gene disruption of 12/15 lipoxygenase (LOX) that metabolizes arachidonate (A) into 12(S)- and 15(S)-HETE minimizes Ang II-induced hypertension in male mice. We performed this study to determine if 2-ME generated by CYP1B1 from E2 mediates its protective effect against Ang II-induced hypertension via LOX inhibition in female mice. Systolic blood pressure (SBP, mmHg, tail-cuff) in response to Ang II (700 ng/Kg/min, sc, miniosmotic pump, 2 weeks) was greater ( P <0.05, n=4-5) in ovariectomized (OVX) than intact Cyp1b1 +/+ / Alox15 +/+ (174±2 vs 135±5), and intact or OVX- Cyp1b1 +/+ / Alox15 –/– (120±4 and 125±5) mice. Moreover, SBP in response to Ang II was greater in trans-2,3',4,5'-tetramethoxystilbene (CYP1B1 inhibitor, 300 μg/Kg, every 3rd day, ip)-treated intact Cyp1b1 +/+ / Alox15 +/+ than Cyp1b1 +/+ / Alox15 –/– (164±3 vs 132±3, n=6-8, P <0.05) mice. Also, mean arterial pressure (MAP, mmHg, radiotelemetry) and low frequency to high-frequency oscillation ratio (LF/HF ratio, power spectral analysis), the index of baroreflex sensitivity impairment, in response to Ang II was greater ( P <0.05, n=4) in OVX- Cyp1b1 +/+ / Alox 15 +/+ (160±3; 2.9±0.1) than in OVX- Cyp1b1 +/+ / Alox15 –/– (119±7; 2±0.1) mice. However, MAP and LF/HF ratio in response to Ang II was lower in 2ME (1.5 mg/g, every 3rd day, ip)-treated OVX- Cyp1b1 +/+ / Alox15 +/+ (108±3; 1.6±0.1) and OVX- Cyp1b1 +/+ / Alox 15 –/– (107±2; 1.6±0.1) mice (n=4). Plasma12(S)-HETE level (ELISA), and renal injury assessed by urine albumin/creatinine ratio in response to Ang II was lower in 2ME than its vehicle (dimethyl sulfoxide)-treated OVX- Cyp1b1 +/+ / Alox 15 +/+ mice (1616±30 vs 2162±55, pg/mL, and 2.7±0.3 vs 1.9±0.1; n=4, P <0.05). Ang II did not increase 12(S)-HETE or albumin/creatinine ratio in Cyp1b1 +/+ / Alo x 15 –/– mice. These data suggest that that E2-CYP1B1 generated metabolite 2ME by inhibiting A-LOX signaling protects against Ang II-induced hypertension, impaired baroreflex, and renal injury in female mice. Therefore, LOX inhibitors could be useful in the treatment of Ang II-induced hypertension and associated renal injury in females.

Cytochrome P450-Dependent Renal Metabolism of Arachidonic Acid in a Rat Model of Angiotensin II induced Hypertension and End-Organ Damage

2002 ◽  
Vol 2002 (Fall) ◽  
Author(s):  
Eva K??rgel ◽  
Horst Honeck ◽  
Dominik N. M??ller ◽  
J??rgen Theuer ◽  
Friedrich C. Luft ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Cytochrome P450 ◽  
Angiotensin Ii ◽  
Rat Model ◽  
Organ Damage ◽  
Renal Metabolism ◽  
End Organ Damage ◽  
Induced Hypertension

scholarly journals Augmenting Renal Lymphatic Density Prevents Angiotensin II-Induced Hypertension in Male and Female Mice

2019 ◽  
Vol 33 (1) ◽  
pp. 61-69 ◽  
Author(s):  
Dakshnapriya Balasubbramanian ◽  
Catalina A Lopez Gelston ◽  
Alexandra H Lopez ◽  
Geina Iskander ◽  
Winter Tate ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Lymphatic Vessel ◽  
Immune Cell ◽  
Peritoneal Macrophages ◽  
Lymphatic Endothelial Cells ◽  
Male And Female ◽  
Female Mice ◽  
Induced Hypertension ◽  
Lymphatic Density

Abstract BACKGROUND Renal inflammation and immune cell infiltration are characteristic of several forms of hypertension. Our laboratory has previously demonstrated that renal-inflammation-associated lymphangiogenesis occurs in salt-sensitive and nitric-oxide-inhibition-induced hypertension. Moreover, enhancing renal lymphatic density prevented the development of these two forms of hypertension. Here, we investigated the effects of angiotensin II-induced hypertension on renal lymphatic vessel density in male and female mice. METHODS Wild-type and genetically engineered male and female mice were infused with angiotensin II for 2 or 3 weeks. Isolated splenocytes and peritoneal macrophages from mice, and commercially available mouse lymphatic endothelial cells were used for in vitro studies. RESULTS Compared to vehicle controls, angiotensin II-infused male and female mice had significantly increased renal lymphatic vessel density in association with pro-inflammatory immune cells in the kidneys of these mice. Direct treatment of lymphatic endothelial cells with angiotensin II had no effect as they lack angiotensin II receptors; however, angiotensin II treatment of splenocytes and peritoneal macrophages induced secretion of the lymphangiogenic growth factor VEGF-C in vitro. Utilizing our genetic mouse model of inducible renal lymphangiogenesis, we demonstrated that greatly augmenting renal lymphatic density prior to angiotensin II infusion prevented the development of hypertension in male and female mice and this was associated with a reduction in renal CD11c+F4/80- monocytes. CONCLUSION Renal lymphatics play a significant role in renal immune cell trafficking and blood pressure regulation, and represent a novel avenue of therapy for hypertension.

Female Mice Are Resistant to Inward Remodeling of Parenchymal Arterioles Observed in Male Mice During Angiotensin II‐Induced Hypertension

2020 ◽  
Vol 34 (S1) ◽  
pp. 1-1
Author(s):  
Laura C. Chambers ◽  
Janice M. Diaz-Otero ◽  
Ting-Chieh Yen ◽  
William F. Jackson ◽  
Anne M. Dorrance
Keyword(s):  
Angiotensin Ii ◽  
Male Mice ◽  
Female Mice ◽  
Induced Hypertension
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