Ovariectomy Via 12/15-lipoxygenase Augments Angiotensin II-Induced Hypertension and Its Pathogenesis in Female Mice.

BACKGROUND: Ang II (angiotensin II) releases arachidonic acid from tissue phospholipids that is metabolized by 12/15-lipoxygenase (ALOX15), generating 12(S)- and 15(S)-hydroxyeicosatetraenoic acid (HETE), which have been implicated in cardiovascular and renal diseases. In this study, we tested the hypothesis that ovariectomy augments Ang II-induced hypertension and renal pathophysiological changes via ALOX15 activation in female mice. METHODS: Ang II (700 ng/kg/min) was infused subcutaneously by osmotic pumps for 2 weeks in intact and ovariectomized wild-type and Alox15 knockout (ALOX15KO) female mice for evaluation of hypertension and associated pathogenesis. RESULTS: Ang II increased blood pressure, impaired autonomic function, and increased renal reactive oxygen species production and plasma 12(S)-HETE level without altering renal function in intact wild-type mice. However, in OVX-wild-type mice with depleted plasma 17ß-estradiol, the effects of Ang II on blood pressure, autonomic impairment, renal reactive oxygen species production, and plasma 12(S)- but not 15(S)-HETE was markedly enhanced. In OVX-wild-type mice, Ang II also increased renal alox15 mRNA, urine 12(S)-HETE, water intake, urine output, decreased osmolality, increased urinary excretion of vasopressin prosegment copeptin, protein/creatinine ratio, and caused renal hypertrophy, fibrosis, and inflammation. These effects of Ang II were attenuated in ALOX15KO mice. CONCLUSIONS: These data suggest that 17ß-estradiol protects against Ang II-induced hypertension and associated pathogenesis in female mice, most likely via inhibition of ALOX15-arachidonic acid derived production of 12(S)-HETE. Therefore, the selective inhibitors of ALOX15 or 12(S)-HETE receptor antagonists could be useful for treating hypertension and its pathogenesis in postmenopausal, hypoestrogenic women, or females with ovarian failure.

2-Methoxyestradiol Ameliorates Angiotensin II-Induced Hypertension by Inhibiting Cytosolic Phospholipase A2α Activity in Female Mice.

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6ß-Hydroxytestosterone Promotes Angiotensin II-Induced Hypertension via Enhanced Cytosolic Phospholipase A2α Activity.

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Testosterone Metabolite 6ß-Hydroxytestosterone Contributes to Angiotensin II-Induced Abdominal Aortic Aneurysms in Apoe-/- Male Mice.

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, 6ß-hydroxytestosterone (6ß-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 6ß-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 6ß-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 6ß-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 6ß-OHT contributes to Ang II-induced AAA development in Apoe-/- male mice.

Gastric mucosal protection by aegle marmelos against gastric mucosal damage: role of enterochromaffin cell and serotonin.

BACKGROUND/AIMS: Serotonin (5-hydroxytryptamine; 5-HT) released from enterochromaffin (EC) cells in gastric mucosa inhibits gastric acidity by increasing the gastric mucus secretion. In the present study, we evaluated the effect of aqueous extract of Aegle marmelos (AM) ripe fruit pulp (250 mg/kg body weight) on mean ulcer index (MUI), EC cells, 5-HT content, and adherent mucosal thickness of ulcerated gastric tissue in adult albino rats. MATERIAL AND METHODS: Ulceration was induced by using aspirin (500 mg/kg, p.o.), cerebellar nodular lesion and applying cold-restraint stress. RESULTS: In all cases increased MUI in gastric tissue along with decreased EC cell count was observed with concomitant decrease of 5-HT content and adherent mucosal thickness (P < 0.05). Pretreatment with AM for 14 days decreased MUI, increased EC cell count, and 5-HT content as well as adherent mucosal thickness in all ulcerated group (P < 0.05). CONCLUSION: AM produces gastric mucosal protection mediated by increased EC cell count and 5-HT levels.