# Angiotensins, Prostaglandins and Adrenergic Interactions

> **NIH NIH R01** · UNIVERSITY OF TENNESSEE HEALTH SCI CTR · 2024 · $747,893

## Abstract

This proposal is aimed to test our novel hypothesis that the cytochrome P450 (CYP)1B1-generated
metabolites of 17b-estradiol (E2) (2-methoxyestradiol, 2-ME) and testosterone (T) (6b-hydroxytestosterone,
6b-OHT) inhibit and enhance, respectively, Ang II-induced production of prohypertensive arachidonic acid
(AA)-12/15 lipoxygenase (ALOX15)/12(S)-hydroxyeicosatetraenoic acid (HETE) and Cyp4a/20-HETE
metabolites in the paraventricular nucleus (PVN) and that this mechanism accounts for the sex differences in
Ang II-induced hypertension, i.e., a lesser increase in blood pressure (BP) in females than males. This
hypothesis is based on our compelling preliminary data that transduction of PVN with adenovirus (Ad)-
ALOX15, and Ad-Cyp4a10/Cyp4a12a-shRNA, respectively, a) ameliorate Ang II-induced increase in BP in
both wild-type (WT) female and male mice; b) attenuate the effect of Ang II to enhance BP, in CYP1B1 gene
disrupted (Cyp1b1–/–) female mice that lack 2-ME; and c) minimize the 6b-OHT effect to restore Ang II-induced
increase in BP that is diminished in Cyp1b1–/– male mice lacking endogenous 6b-OHT. We will expand these
observations to test our hypothesis by addressing the following specific aims. Aim 1. To determine contribution
of the central AA/LOX15 system to Ang II-induced hypertension and its pathogenesis in female and male mice.
Sub-Aim 1. To examine interaction of the central AA/LOX15 system and CYP1B1-generated E2 and T
metabolites in Ang II-induced hypertension and its pathogenesis in female and male mice. Aim 2. To examine
contribution of the central AA/Cyp4a10 and Cyp4a12a systems to Ang II-induced hypertension and its
pathogenesis in female and male mice. Sub-Aim 2. To determine interaction of the central AA/Cyp4a10 and
Cyp4a12a systems and CYP1B1-generated E2 and T metabolites in Ang II-induced hypertension and its
pathogenesis in females and male mice. To achieve these aims, we will use the state-of-the-art techniques,
which include: a) Radiotelemetry for measuring BP; b) wild-type and Alox15–/–, Cyp1b1–/–, and cPLA2a–/–
female and male mice; c) Ad-ALOX15-shRNA, Ad-Cyp4a10, and Ad-Cyp4a12a-shRNA and respective Ad-
scrambled shRNA controls, and their Ad-DNA and Ad-GFP-DNA control, and 12(S)-HETE Gpr31 and Ltb4r2
and 20-HETE Gpr75 receptor siRNAs and their non-target siRNA; d) Histological, immunohistochemical, and
fluorescence microscopy and biochemical techniques; e) Flow cytometry to determine immune cell infiltration
in aorta, kidney and brain; f) UPLC/qTOF MS for the analysis of sex steroids and eicosanoids. The proposed
studies will provide insights into the molecular mechanism underlying sex differences determined by the
interaction of CYP1B1-generated metabolites of sex steroids and AA/ALOX15- and Cyp4a systems in the PVN
in Ang II-induced hypertension and associated pathogenesis. Moreover, these studies should identify central
ALOX15 and Cyp4a as a potential site of action of the selective inhibitors of these enzyme systems a...

## Key facts

- **NIH application ID:** 10815585
- **Project number:** 5R01HL019134-48
- **Recipient organization:** UNIVERSITY OF TENNESSEE HEALTH SCI CTR
- **Principal Investigator:** KAFAIT U MALIK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $747,893
- **Award type:** 5
- **Project period:** 1977-09-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10815585

## Citation

> US National Institutes of Health, RePORTER application 10815585, Angiotensins, Prostaglandins and Adrenergic Interactions (5R01HL019134-48). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10815585. Licensed CC0.

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