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.

Abstract 252: 6ß-Hydroxytestosterone, A Cytochrome P450 1B1 Metabolite of Testosterone, Enhances Angiotensin II-Induced Pressor Effect in Male Mice

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Ajeeth K Pingili ◽  
Brett L Jennings ◽  
Nayaab S Khan ◽  
Kafait U Malik
Keyword(s):  
Cytochrome P450 ◽  
Endothelial Dysfunction ◽  
Ros Production ◽  
Oxygen Species ◽  
Pressor Effect ◽  
Ang Ii ◽  
Male Mice ◽  
Cytochrome P450 1B1 ◽  
Induced Hypertension ◽  
Novel Target

Androgens have been implicated in the development of hypertension and castration minimizes the pressor effect of angiotensin (Ang) II. Previously we showed that Ang II-induced hypertension and associated pathophysiological changes are diminished in male cytochrome P450 (CYP) 1B1 gene disrupted mice. Since CYP1B1 metabolizes testosterone to 6β-hydroxytestosterone (6β-OHT); this study was conducted to determine its contribution in modulation of Ang II-induced hypertension. Eight weeks old male Cyp1b1+/+ and Cyp1b1-/- mice were either castrated or injected with 6β-OHT (15 μg/g, i.p. every 3rd day) or vehicle (DMSO, 50 μl), infused with Ang II (700 ng/kg/min) or vehicle for 2 weeks, and systolic blood pressure (SBP) was measured by tail cuff. Castration attenuated Ang II-induced increase in SBP in both Cyp1b1+/+ (184 ± 6 vs. 129 ± 4 mmHg, P < 0.05) and Cyp1b1-/- mice (150 ± 6 vs. 129 ± 4 mmHg, P < 0.05). In Cyp1b1+/+ mice, 6β-OHT did not alter Ang II-induced increase in SBP (184 ± 6 vs. 180 ± 8 mmHg, P < 0.05), but enhanced it in Cyp1b1-/- mice (150 ± 6 vs. 172 ± 8 mmHg, P < 0.05). Castration improved endothelial dysfunction associated with Ang II-induced hypertension in Cyp1b1+/+ mice, as demonstrated by increased relaxation of the aorta to acetylcholine. No endothelial dysfunction was observed in Cyp1b1-/- mice given Ang II with or without castration. In Cyp1b1+/+ mice, 6β-OHT did not alter Ang II-induced endothelial dysfunction, however, in Cyp1b1-/- mice infused with Ang II, 6β-OHT caused endothelial dysfunction. We have shown that Ang II-induced hypertension is associated with increased vascular production of reactive oxygen species (ROS) in Cyp1b1+/+ mice, and this increase is attenuated in Cyp1b1-/- mice, as measured by dihydroethidium fluorescence. In both Cyp1b1+/+ and Cyp1b1-/- mice given Ang II, castration abolished the increased ROS production. In Cyp1b1+/+ mice, 6β-OHT did not alter levels of ROS produced by Ang II, however, 6β-OHT further increased ROS production in Cyp1b1-/- mice given Ang II. These data suggest that 6β-OHT, a CYP1B1 metabolite of testosterone, contributes to the hypertensive effect of Ang II in male mice. Moreover, CYP1B1 could serve as a novel target for the development of agents for the treatment of androgen-mediated hypertension.

Abstract 341: Cytochrome P450 1b1 Is Essential For The Development Of Aortic Aneurysm In Apoe Knockout Mice

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Shyamala Thirunavukkarasu ◽  
Nayaab S Khan ◽  
Hafiz U Ghafoor ◽  
Brett L Jennings ◽  
Kamalika Mukherjee ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Gene Deletion ◽  
Growth Factor Receptor ◽  
Abdominal Aortic Aneurysms ◽  
Aortic Aneurysms ◽  
Ang Ii ◽  
Simultaneous Treatment ◽  
Markers Of Inflammation ◽  
Cyp1b1 Gene ◽  
Abdominal Aortic

Previously we showed that the development of hypertension is dependent on cytochrome P450 (CYP)1B1 activity. This study addressed the role of CYP1B1 in the pathogenesis of angiotensin II (Ang II)-induced aortic aneurysms. Sixteen week old male ApoE-/-/Cyp1b1+/+ and ApoE-/-/Cyp1b1-/- mice were administered Ang II (700 ng/min/Kg) or its vehicle (veh) for one month using mini-osmotic pumps implanted subcutaneously. A separate group of ApoE-/-/Cyp1b1+/+ mice receiving Ang II were injected twice weekly with the selective inhibitor of CYP1B1 2,3',4,5'-tetramethoxystilbene (TMS) (300 μg/Kg) or its vehicle DMSO (i.p.). Ultrasound studies showed that Ang II infusion produced abdominal aortic aneurysms in the ApoE-/-/Cyp1b1+/+ mice that were prevented by simultaneous treatment with TMS or Cyp1b1 gene deletion. Ang II-induced aortic aneurysms were characterized by increased degradation of collagen, elastin and actin; and expression of matrix metalloproteinases MMP2, 9 as well as markers of inflammation including macrophages, and CD3+ T cells, and increased production of reactive oxygen species in the ApoE-/-/Cyp1b1+/+ mice; these changes were minimized by treatment with TMS or Cyp1b1 gene deletion (Table 1). Microarray analysis indicated downregulation (>1.5 fold) of markers of angiogenesis and inflammation including Angiopoeitin 2, P-selectin, platelet derived growth factor receptor, MMP 2, 9 and 12, and CD276 in the ApoE-/-/Cyp1b1-/- mice. These data suggest that Ang II-induced abdominal aortic aneurysms and associated pathophysiological changes in ApoE-/- mice are mediated by CYP1B1 via increased inflammation and oxidative stress.

Abstract 250: 6β-hydroxytestosterone, A Cytochrome P450 1b1-derived Metabolite Of Testosterone, Mediates Increase In Thirst, Renal Dysfunction, And End Organ Damage Associated With Angiotensin II-induced Hypertension In Male Mice

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Ajeeth K Pingili ◽  
Mehmet Kara ◽  
Brett L Jennings ◽  
Anne M Estes ◽  
Kafait U Malik
Keyword(s):  
Oxidative Stress ◽  
Renal Function ◽  
Cytochrome P450 ◽  
Renal Fibrosis ◽  
Organ Damage ◽  
Ang Ii ◽  
Male Mice ◽  
End Organ Damage ◽  
Cytochrome P450 1B1 ◽  
Induced Hypertension

Recently, we showed that 6β-hydroxytestosterone (6β-OHT), a cytochrome P450 1B1 (CYP1B1)-derived metabolite of testosterone, contributes to the development of angiotensin II (Ang II)-induced hypertension and associated cardiovascular pathophysiology. In view of the critical role of Ang II in renal homeostasis and end organ damage, we determined the contribution of 6β-OHT to Ang II actions on water consumption and renal function in male Cyp1b1 +/+ and Cyp1b1 -/- mice. Eight weeks old male Cyp1b1 +/+ and Cyp1b1 -/- intact or castrated mice were injected with 6β-OHT (15 μg/g, i.p. every 3 rd day) or vehicle (DMSO, 50 μl), and infused with Ang II (700 ng/kg/min) or vehicle for 2 weeks. Urine was collected for 24 hours on the final day of experiment. Castration attenuated Ang II-induced increase in water consumption and urine output, proteinuria and decrease in osmolality in both Cyp1b1 +/+ , and Cyp1b1 -/- mice (Table 1). 6β-OHT did not alter Ang II-induced increase in water intake, urine output, proteinuria and decrease in osmolality in Cyp1b1 +/+ mice, but restored these effects of Ang II in Cyp1b1 -/- or castrated mice (Table 1). Cyp1b1 gene disruption or castration prevented Ang II-induced renal fibrosis, inflammation, and oxidative stress. 6β-OHT did not alter Ang II-induced renal fibrosis, inflammation or oxidative stress in Cyp1b1 +/+ mice, however in Cyp1b1 -/- or castrated mice it restored these effects of Ang II. These data suggest that 6β-OHT, contributes to increased thirst, impairment of renal function and end organ damage associated with Ang II-induced hypertension in male mice, and that CYP1B1 could serve as a novel target for the treatment of renal disease and 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

scholarly journals Castration of male mice prevents the progression of established angiotensin II-induced abdominal aortic aneurysms

2015 ◽  
Vol 61 (3) ◽  
pp. 767-776 ◽  
Author(s):  
Xuan Zhang ◽  
Sean Thatcher ◽  
Congqing Wu ◽  
Alan Daugherty ◽  
Lisa A. Cassis
Keyword(s):  
Angiotensin Ii ◽  
Abdominal Aortic Aneurysms ◽  
Aortic Aneurysms ◽  
Male Mice ◽  
Abdominal Aortic

Abstract 100: An XY Sex Chromosome Complement in Females Confers Susceptibility and Rupture of Angiotensin II-induced Abdominal Aortic Aneurysms in Hypercholesterolemic Female Mice

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Yasir Alsiraj ◽  
Sean Thatcher ◽  
Eric Blalock ◽  
Kuey Chen ◽  
Richard Charnigo ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Y Chromosome ◽  
Dna Microarrays ◽  
Sex Chromosome ◽  
Chromosome Complement ◽  
Abdominal Aortic Aneurysms ◽  
Aortic Aneurysms ◽  
Male Mice ◽  
Female Mice ◽  
Abdominal Aortic

Objective: We previously demonstrated that female mice are less susceptible to angiotensin II (AngII)-induced abdominal aortic aneurysms (AAAs) compared to males, a sex difference present in humans. Sex chromosome abnormalities, such as Turner’s syndrome (monosomy X), are associated with aortic vascular disease. In this study, we tested the hypothesis that an XY sex chromosome complement in females promotes AngII-induced AAAs. In addition, as previous studies demonstrated that testosterone promotes AngII-induced AAAs in male mice, we determined if testosterone would augment AAA severity in XY females. Methods and Results: Transgenic male mice with deletion of Sry from the Y-chromosome expressing Sry on autosomes (8-12 weeks of age) were bred to female Ldlr-/- mice to generate female mice with an XY or an XX sex chromosome complement. Female mice (XX and XY) were fed a Western diet and segregated into sham and ovariectomized (OVX) groups. Two weeks later, mice were implanted with osmotic minipumps to infuse AngII (1,000 ng/kg/min) for 28 days. The AAA incidence (XX sham, 40%; XX OVX 29%; XY sham, 71%; XY OVX, 57%, p=0.031) and rupture rate (XX sham, 0%; XX OVX 0%; XY sham, 35%; XY OVX, 29%, p=0.003) were significantly increased in XY compared to XX females. Internal abdominal aortic lumen diameters were significantly increased in XY OVX versus XX OVX female mice at day 27 (XY, 2.31 ± 0.14; XX, 1.58 ± 0.2, p= 0.009). Moreover, AAA external diameters were significantly increased in XY OVX versus XX OVX females (XY, 2.34 ± 0.15; XX, 1.71 ± 0.18, p=0.0004). Administration of testosterone to adult female XY mice as well as neonatal female mice markedly enhanced AAA rupture (maximum of 73%). DNA microarrays of abdominal aortas revealed that male specific genes on the Y chromosome and inflammatory genes were enriched in aortas from XY females, while genes that escape X-inactivation were enriched in aortas from XX females. Conclusion: These results demonstrate that an XY sex chromosome complement is sufficient to promote a high AAA incidence, and markedly increase AAA severity in female mice. Moreover, testosterone augmented AAA ruptures in XY females. Future studies will identify gene targets influenced by sex chromosome complement and/or testosterone.

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 Weight loss in obese C57BL/6 mice limits adventitial expansion of established angiotensin II-induced abdominal aortic aneurysms

2010 ◽  
Vol 298 (6) ◽  
pp. H1932-H1938 ◽  
Author(s):  
Sara B. Police ◽  
Kelly Putnam ◽  
Sean Thatcher ◽  
Frederique Batifoulier-Yiannikouris ◽  
Alan Daugherty ◽  
...  
Keyword(s):  
Weight Loss ◽  
Angiotensin Ii ◽  
Abdominal Aortic Aneurysms ◽  
Aortic Aneurysms ◽  
Stem Cell Marker ◽  
Ang Ii ◽  
Low Fat Diet ◽  
Abdominal Aortic ◽  
Induce Weight Loss ◽  
Adipose Derived Stem Cell

Previous studies demonstrated that obesity increases inflammation in periaortic adipose tissue and promotes angiotensin II (ANG II)-induced abdominal aortic aneurysms (AAAs). We sought to determine whether weight loss of obese C57BL/6 mice would influence the progression of established AAAs. Male C57BL/6 mice were fed a high-fat diet (HF) for 4 mo and then infused with either saline or ANG II (1,000 ng·kg−1·min−1) for 3 mo. Mice with dilated suprarenal aortas at 28 days of ANG II infusion were designated to groups fed the HF (HF/HF) or a low-fat diet (LF; 10% kcal as fat; HF/LF) to induce weight loss for the last 2 mo of infusions. Suprarenal aortic lumen diameters of obese mice were increased by ANG II infusion at day 28 ( day 0: 1.03 ± 0.02; day 28: 1.86 ± 0.14 mm; P < 0.05), but did not progress with continued infusion in HF/HF mice. Moreover, aortic lumen diameters were not different between groups (HF/HF: 1.89 ± 0.15; HF/LF: 1.79 ± 0.18 mm). However, maximal diameters of excised AAAs were decreased with weight loss (HF/HF: 2.00 ± 0.11; HF/LF: 1.55 ± 0.13 mm; P < 0.05) and had reduced adventitial areas (HF/HF: 1.18 ± 0.10; HF/LF: 0.54 ± 0.02 mm2; P < 0.05). Neovascularization of aortic adventitias was strikingly decreased in HF/LF mice (HF/HF: 43 ± 5; HF/LF: 12 ± 2 endothelial cells/adventitial area; P < 0.05). ANG II-induced elevations in adipose mRNA abundance of CD105, an adipose-derived stem cell marker, were abolished with weight loss. These results demonstrate that weight loss limits adventitial expansion of ANG II-induced AAAs. Reduced neovascularization from weight loss may limit progression of AAAs.

scholarly journals Efficacy and Mechanism of Angiotensin II Receptor Blocker Treatment in Experimental Abdominal Aortic Aneurysms

PLoS ONE ◽  
2012 ◽  
Vol 7 (12) ◽  
pp. e49642 ◽  
Author(s):  
Yasunori Iida ◽  
Baohui Xu ◽  
Geoffrey M. Schultz ◽  
Vinca Chow ◽  
Julie J. White ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Abdominal Aortic Aneurysms ◽  
Aortic Aneurysms ◽  
Receptor Blocker ◽  
Angiotensin Ii Receptor Blocker ◽  
Angiotensin Ii Receptor ◽  
Abdominal Aortic

Abstract 1684: Toll-like Receptor 4 Deficiency Attenuates Angiotensin II-induced Atherosclerosis and Abdominal Aortic Aneurysms via a MyD88-dependent Mechanism

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
A. Phillip Owens ◽  
Deborah A Howatt ◽  
Alan Daugherty
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Systolic Blood Pressure ◽  
Atherosclerotic Lesion ◽  
Abdominal Aortic Aneurysms ◽  
Aortic Aneurysms ◽  
Vascular Pathology ◽  
Toll Like Receptor ◽  
Abdominal Aortic ◽  
Post Infusion

Objective: We previously demonstrated that angiotensin II (AngII) infusion into myeloid differentiation factor 88 deficient mice (MyD88−/−) resulted in a profound reduction of atherosclerosis and abdominal aortic aneurysms (AAAs) in apoE−/− mice. Furthermore, AngII directly regulated toll-like receptor (TLR) mRNA in cell types associated with these diseases. The objective of this study was to determine the specific TLR responsible for the MyD88 mediated reduction in vascular pathology. Methods and Results: MyD88 mice were bred onto an LDLr−/− background. Deficiency in this hyperlipidemic strain caused similar decreases in AngII-induced atherosclerosis and aneurysm to those we previously noted in apoE−/− mice. Male TLR4+/+ (n = 14) or −/− (n = 19), on an LDLr−/− background, were fed a fat-enriched diet (21% milk fat, 0.15% cholesterol) and infused with AngII (1,000ng/kg/min) for 28 days. TLR4−/− mice had significantly attenuated systolic blood pressure from TLR4+/+ mice both prior to and during AngII infusion (P < .01). However, AngII did increase systolic blood pressure similarly in both groups (+/+: pre-infusion 142 ± 2, post-infusion 169 ± 3 mmHg; −/−: pre-infusion 130 ± 1, post-infusion 158 ± 3 mmHg; P < .001). Neither TLR4 genotype nor AngII infusions had significantly different effects on total plasma cholesterol concentrations or lipoprotein-cholesterol distributions. TLR4 deficiency dramatically decreased AngII-induced atherosclerotic lesion areas in both the aortic arch (50% decrease, P < .004), and thoracic aorta (66% decrease, P < .001). TLR4 deficiency decreased the diameter of the suprarenal abdominal aortic region from 2.31 ± 0.3 to 1.2 ± 0.06 mm (P < 0.001) and the incidence of AAAs from 93% to 26% (P < 0.001), versus control animals. Conversely, TLR2 deficiency reduced AngII-induced atherosclerosis in LDLr−/− mice, but had no significant effect on AAA formation. Conclusion: TLR4 deficiency attenuated both AngII-induced atherosclerosis and AAAs, in LDLr−/− mice, in a manner similar to the effects of MyD88 deficiency. TLR2 deficiency decreased AngII-induced atherosclerosis, but had no effect on AAAs. These data are consistent with TLR4 being the major receptor for MyD88-induced effects on AngII-induced AAAs. This research has received full or partial funding support from the American Heart Association, AHA Great Rivers Affiliate (Delaware, Kentucky, Ohio, Pennsylvania & West Virginia).

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