Abstract P303: Inhibition of Group IV Cytosolic Phospholipase A 2 α by Cytochrome P450 1B1-Estradiol Derived Metabolite 2-Methoxyestradiol Protects Against Angiotensin II-Induced Hypertension in Female Mice

Hypertension ◽  
2018 ◽  
Vol 72 (Suppl_1) ◽  
Author(s):  
Chi Young Song ◽  
Purnima Singh ◽  
Mustafa Motiwala ◽  
Ji Soo Shin ◽  
Joseph V Bonventre ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Angiotensin Ii ◽  
Group Iv ◽  
Phospholipase A ◽  
Female Mice ◽  
Cytochrome P450 1B1 ◽  
Cytosolic Phospholipase ◽  
Induced Hypertension ◽  
Phospholipase A 2

Abstract MP63: Cytochrome P450 1B1 Mediated Inhibition Of Group IV Cytosolic Phospholipase A 2 α In Paraventricular Nucleus Protects Female Mice From Angiotensin II-Induced Hypertension, Increased Renal Sympathetic Activity And Proteinuria

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Purnima Singh ◽  
Shubha Ranjan Dutta ◽  
ChiYoung Song ◽  
Kafait U Malik
Keyword(s):  
Cytochrome P450 ◽  
Sympathetic Activity ◽  
Group Iv ◽  
Ang Ii ◽  
Female Mice ◽  
Cytochrome P450 1B1 ◽  
Cytosolic Phospholipase ◽  
Induced Hypertension ◽  
Α Activity ◽  
Renal Sympathetic

Recently we showed that 2-methoxyestradiol (2-ME), an estrogen (E2) metabolite generated by CYP1B1 (cytochrome P450 1B1) in the paraventricular nucleus (PVN), protects female mice from Ang (angiotensin) II-induced hypertension and increased renal sympathetic activity. We also demonstrated that group IV cPLA 2 α (cytosolic phospholipase A 2 α) in the brain contributes to Ang II-induced hypertension in male mice. This study was conducted to determine the contribution of central cPLA 2 α and its relationship to CYP1B1 in Ang II-induced hypertension in female mice. cPLA 2 α knockdown in the PVN by transduction with adenovirus (Ad)-cPLA 2 α-short hairpin (sh)RNA (200 nL, bilaterally, 1.0х10 12 pfu/mL) but not its control Ad-scrambled (Scr)-shRNA (2.5х10 11 pfu/mL) in ovariectomized (OVX) wild-type ( cPLA 2 α +/+ / Cyp1b1 +/+ , n=8/group) and intact cPLA 2 α +/+ / Cyp1b1 -/- (n=12/group) female mice attenuated the effect of Ang II (700 ng/kg/min, subcutaneous, osmotic pump, 2 weeks) to increase the systolic blood pressure (SBP, mmHg) as measured by tail-cuff (Day 12: 129±3 vs 168±7 and 119±3 vs 172±5, respectively, P<0.05). Moreover, reconstitution of cPLA 2 α in the PVN by transduction with Ad-cPLA 2 α-DNA (1.1х10 12 pfu/mL) but not its control Ad-GFP-DNA (1.0х10 11 pfu/mL) in OVX- cPLA 2 α -/- / Cyp1b1 +/+ mice (n=4/group) restored the effect of Ang II to increase SBP (Day 12: 163±7 vs 124±4, P<0.05). Furthermore, Ad-cPLA 2 α-shRNA but not Ad-Scr-shRNA transduction in the PVN in OVX- cPLA 2 α +/+ / Cyp1b1 +/+ and intact cPLA 2 α +/+ / Cyp1b1 -/- mice reduced and Ad-cPLA 2 α-DNA but not Ad-GFP-DNA transduction in the PVN in OVX- cPLA 2 α -/- / Cyp1b1 +/+ mice restored the effect of Ang II to increase the renal sympathetic activity as indicated by urinary norepinephrine level (ng/mL, 324±36 vs 707±94, 359±49 vs 979±70, 690±44 vs 421±43, respectively, n=4/group, P<0.05) and proteinuria (mg/24 hour, 4±1 vs 10±0.4, 3±0.4 vs 7±1, 9±0.8 vs 3±0.7, respectively, n=4/group, P<0.05). These data suggest that E2-CYP1B1 derived metabolite 2-ME protects against Ang II-induced hypertension, renal sympathetic activity, and proteinuria by inhibiting cPLA 2 α activity in the PVN. Thus, 2-ME and/or agents inhibiting cPLA 2 α activity could be useful for treating hypertension and its pathogenesis in females.

scholarly journals Cytosolic Phospholipase A 2 α Is Critical for Angiotensin II–Induced Hypertension and Associated Cardiovascular Pathophysiology

Hypertension ◽  
2015 ◽  
Vol 65 (4) ◽  
pp. 784-792 ◽  
Author(s):  
Nayaab S. Khan ◽  
Chi Young Song ◽  
Brett L. Jennings ◽  
Anne M. Estes ◽  
Xiao R. Fang ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Phospholipase A ◽  
Cytosolic Phospholipase ◽  
Induced Hypertension ◽  
Phospholipase A 2

Abstract 155: Group IV Cytosolic Phospholipase A 2 a Disruption Protects Against Angiotensin II-Induced Hypertension and End Organ Damage

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Nayaab S Khan ◽  
Chi Young Song ◽  
Joseph V Bonventre ◽  
Kafait U Malik
Keyword(s):  
Renal Dysfunction ◽  
Water Intake ◽  
Urine Output ◽  
Organ Damage ◽  
Group Iv ◽  
Phospholipase A ◽  
Ang Ii ◽  
End Organ Damage ◽  
Cytosolic Phospholipase ◽  
Induced Hypertension

Previously we have shown that Group IV cytosolic phospholipase A 2 α (cPLA 2 α) is critical for the development of angiotensin (Ang) II-induced hypertension, cardiovascular dysfunction and fibrosis. This study was conducted to determine the role of cPLA 2 α in renal dysfunction and end organ damage associated with Ang II-induced hypertension. Eight weeks old male wild type (cPLA 2 α +/+ ) and cPLA 2 α knockout (cPLA 2 α -/- ) mice were infused with Ang II (700 ng/kg/min) or its vehicle for 2 weeks and systolic blood pressure (SBP) was measured weekly by the tail cuff method. Ang II increased SBP (mmHg) in cPLA 2 α +/+ mice to a greater degree than in cPLA 2 α -/- mice (125 ± 2 to 186 ± 7 vs. 125 ± 2 to 132 ± 2 respectively, P< 0.05). Ang II caused renal fibrosis as indicated by accumulation of α-smooth muscle actin, transforming growth factor-β-positive cells and collagen deposition in the kidneys of cPLA 2 α +/+ but not cPLA 2 α -/- mice. Ang II infusion increased reactive oxygen species production in the kidney measured by 2-hydroxyethidium fluorescence (AU), in cPLA 2 α +/+ mice (16.14 ± 0.61 vehicle vs. 24.08 ± 0.61 Ang II P < 0.05) but not in cPLA 2 α -/- mice (16.93 ± 0.58 vehicle vs. 17.19 ± 0.93 Ang II). Mice were placed in metabolic cages to monitor their water intake and urine output. After 13 days of Ang II infusion, 24 hr water intake was increased (4.33 ± 0.14 ml to 8.17 ± 0.27 ml P < 0.05) in cPLA 2 α +/+ mice but not in cPLA 2 α -/- mice (4.87 ± 0.22 ml to 4.8 ± 0.27 ml). Twenty-four hr urine output (μl) was increased to a greater extent in cPLA 2 α +/+ mice (423.33 ± 67.26 to 2030.94 ± 191.58 P < 0.05) vs. cPLA 2 α -/- mice (374.37 ± 66.89 to 787.37 ± 126.50). Urine osmolality (mOsm/kg) was decreased (3778.33 ± 240.21 to 1620 ± 129.23 P < 0.05) in cPLA 2 α +/+ but not in cPLA 2 α -/- mice (4042 ± 306.07 to 3372.5 ± 43.27), and proteinuria (mg/24hr) increased to a greater extent in cPLA 2 α +/+ mice (2.07 ± 0.11 to 6.99 ± 0.34 P < 0.05) vs. cPLA 2 α -/- mice (1.95 ± 0.07 to 3.03 ± 0.20 in cPLA 2 α -/- ). These data suggest that cPLA 2 α contributes to Ang II-induced hypertension, associated renal dysfunction and end organ damage, most likely due to release of arachidonic acid, activation of NADPH oxidase and generation of ROS. Thus, cPLA 2 α could serve as a potential therapeutic target in the treatment of hypertension and end organ damage.

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

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

Hypertension ◽  
2014 ◽  
Vol 64 (1) ◽  
pp. 134-140 ◽  
Author(s):  
Brett L. Jennings ◽  
L. Watson George ◽  
Ajeeth K. Pingili ◽  
Nayaab S. Khan ◽  
Anne M. Estes ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Angiotensin Ii ◽  
Estrogen Metabolism ◽  
Female Mice ◽  
Cytochrome P450 1B1

scholarly journals Brain Testosterone-CYP1B1 (Cytochrome P450 1B1) Generated Metabolite 6β-Hydroxytestosterone Promotes Neurogenic Hypertension and Inflammation

Hypertension ◽  
2020 ◽  
Vol 76 (3) ◽  
pp. 1006-1018
Author(s):  
Purnima Singh ◽  
Shubha Ranjan Dutta ◽  
Chi Young Song ◽  
SaeRam Oh ◽  
Frank J. Gonzalez ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Cytochrome P450 ◽  
Angiotensin Ii ◽  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Paraventricular Nucleus ◽  
Male Mice ◽  
Cytochrome P450 1B1 ◽  
Induced Hypertension ◽  
The Brain

Previously, we showed that peripheral administration of 6β-hydroxytestosterone, a CYP1B1 (cytochrome P450 1B1)-generated metabolite of testosterone, promotes angiotensin II-induced hypertension in male mice. However, the site of action and the underlying mechanism by which 6β-hydroxytestosterone contributes to angiotensin II-induced hypertension is not known. Angiotensin II increases blood pressure by its central action, and CYP1B1 is expressed in the brain. This study was conducted to determine whether testosterone-CYP1B1 generated metabolite 6β-hydroxytestosterone locally in the brain promotes the effect of systemic angiotensin II to produce hypertension in male mice. Central CYP1B1 knockdown in wild-type ( Cyp1b1 +/+ ) mice by intracerebroventricular-adenovirus-GFP (green fluorescence protein)-CYP1B1-short hairpin (sh)RNA attenuated, whereas reconstitution of CYP1B1 by adenovirus-GFP-CYP1B1-DNA in the paraventricular nucleus but not in subfornical organ in Cyp1b1 −/− mice restored angiotensin II-induced increase in systolic blood pressure measured by tail-cuff. Intracerebroventricular-testosterone in orchidectomized (Orchi)- Cyp1b1 +/+ but not in Orchi- Cyp1b1 −/− , and intracerebroventricular-6β-hydroxytestosterone in the Orchi- Cyp1b1 −/− mice restored the angiotensin II-induced: (1) increase in mean arterial pressure measured by radiotelemetry, and autonomic imbalance; (2) reactive oxygen species production in the subfornical organ and paraventricular nucleus; (3) activation of microglia and astrocyte, and neuroinflammation in the paraventricular nucleus. The effect of intracerebroventricular-6β-hydroxytestosterone to restore the angiotensin II-induced increase in mean arterial pressure and autonomic imbalance in Orchi- Cyp1b1 −/− mice was inhibited by intracerebroventricular-small interfering (si)RNA-androgen receptor (AR) and GPRC6A (G protein-coupled receptor C6A). These data suggest that testosterone-CYP1B1-generated metabolite 6β-hydroxytestosterone, most likely in the paraventricular nucleus via AR and GPRC6A, contributes to angiotensin II-induced hypertension and neuroinflammation in male mice.

scholarly journals Testosterone Metabolite 6β‐Hydroxytestosterone Contributes to Angiotensin II‐Induced Abdominal Aortic Aneurysms in Apoe –/– Male Mice

2021 ◽  
Author(s):  
Kamalika Mukherjee ◽  
Ajeeth K. Pingili ◽  
Purnima Singh ◽  
Ahmad N. Dhodi ◽  
Shubha R. Dutta ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Risk Factor ◽  
Angiotensin Ii ◽  
Abdominal Aortic Aneurysms ◽  
Aortic Aneurysms ◽  
Ang Ii ◽  
Male Mice ◽  
Cytochrome P450 1B1 ◽  
Abdominal Aortic ◽  
Induced Hypertension

Background Sex is a prominent risk factor for abdominal aortic aneurysms (AAAs), and angiotensin II (Ang II) induces AAA formation to a greater degree in male than in female mice. We previously reported that cytochrome P450 1B1 contributes to the development of hypertension, as well as AAAs, in male mice. We also found that a cytochrome P450 1B1‐generated metabolite of testosterone, 6β‐hydroxytestosterone (6β‐OHT), contributes to Ang II‐induced hypertension and associated cardiovascular and renal pathogenesis in male mice. The current study was conducted to determine the contribution of 6β‐OHT to Ang II‐induced AAA development in Apoe –/– male mice. Methods and Results Intact or castrated Apoe –/– /Cyp1b1 +/+ and Apoe –/– /Cyp1b1 –/– male mice were infused with Ang II or its vehicle for 28 days, and administered 6β‐OHT every third day for the duration of the experiment. Abdominal aortas were then evaluated for development of AAAs. We observed a significant increase in the incidence and severity of AAAs in intact Ang II‐infused Apoe –/– /Cyp1b1 +/+ mice, compared with vehicle‐treated mice, which were minimized in castrated Apoe –/– /Cyp1b1 +/+ and intact Apoe –/– /Cyp1b1 –/– mice infused with Ang II. Treatment with 6β‐OHT significantly restored the incidence and severity of AAAs in Ang II‐infused castrated Apoe –/– /Cyp1b1 +/+ and intact Apoe –/– /Cyp1b1 –/– mice. However, administration of testosterone failed to increase AAA incidence and severity in Ang II‐infused intact Apoe –/– /Cyp1b1 –/– mice. Conclusions Our results indicate that the testosterone‐cytochrome P450 1B1‐generated metabolite 6β‐OHT contributes to Ang II‐induced AAA development in Apoe –/– male mice.

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