# Angiotensins, Prostaglandins-Adrenergic Interactions

> **NIH NIH R01** · UNIVERSITY OF TENNESSEE HEALTH SCI CTR · 2021 · $643,123

## Abstract

This proposal is aimed to test the hypothesis that: Cytochrome P450 (CYP) 1B1-generated metabolites of
estradiol (E2) (2-methoxyestradiol, 2-ME) by inhibiting and testosterone (T) (6β-hydroxytestosterone, 6β-OHT)
by enhancing angiotensin (Ang) II effect on cytosolic phospholipase A2α (cPLA2α) and generation of
cyclooxygenase (COX)- arachidonic acid (AA)-derived prostaglandin (PG) E2 exerting prohypertensive effect
via EP1 and EP3 receptors, protects the female but not males against hypertension and its pathogenesis. This
hypothesis is based on our novel preliminary data that Ang II-induced hypertension in a) ovariectomized (OVX)
or CYP1B1 gene disrupted (Cyp1b1-/-) female mice; and b) castrated (Cas) or Cyp1b1-/- male mice treated with
6β-OHT, is minimized by cPLA2α gene disruption (cPLA2α-/-), by AA metabolism inhibitor 5,8,11,14-
eicosatetraynoic acid (ETYA), or COX-derived PGE2-EP1 and EP3 receptor antagonists. More importantly, our
new observation shows that CYP1B1-generated E2 and T metabolites in the brain mediate the effect of Ang II
on blood pressure (BP) by modulating the activity of cPLA2αAA system in the opposite direction in female
(inhibitory) and male (stimulatory) mice. We will extend these observations and test our hypothesis by
addressing the following specific aims. AIM 1. To determine the interaction of CYP1B1 and cPLA2α/AA system
in Ang II-induced hypertension and its pathogenesis in female mice. Sub-Aim 1. To investigate the contribution
of central cPLA2α/AA system and CYP1B1 and their interaction in Ang II-induced hypertension and its
pathogenesis in female mice. Aim 2. To examine the interaction of CYP1B1 with cPLA2α/AA system in Ang II-
induced hypertension and its pathogenesis in male mice. Sub-Aim 2. To determine the contribution of central
CYP1B1 and its interaction with cPLA2α/AA system in Ang II-induced hypertension and its pathogenesis in
male mice. To achieve these objectives, we will use the state-of-the-art techniques which include: 1) Radio-
telemetry for measuring BP and for power spectral analysis, and Echocardiography for assessing cardiac
function; 3) Cyp1b1+/+ and Cyp1b1-/- and cPLA2α+/+and cPLA2α-/- mice; 2) Adenovirus (Ad) CYP1B1 shRNA
and Ad CYP1B1 DNA, and Adenovirus (Ad) cPLA2α shRNA and Ad cPLA2α DNA, and siRNA for EP1 and
EP3, and steroid genomic and nongenomic receptors, and their respective controls; 4) UPLC/qTOFMS for the
analysis of sex steroids and eicosanoids; 5) histological, immunohistochemical, and fluorescence microscopy
and biochemical techniques; 6) Flow cytometry to determine immune cell population in the blood and tissues.
The proposed studies should provide novel insights into the molecular mechanisms underlying sex differences
as determined by the interaction of CYP1B1-generated metabolites of sex steroids and cPLA2α/AA system in
Ang II-induced hypertension and its pathogenesis. Furthermore, these studies would allow us to demonstrate
cPLA2α as a potential target for developing novel s...

## Key facts

- **NIH application ID:** 10176555
- **Project number:** 5R01HL019134-46
- **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:** 2021
- **Award amount:** $643,123
- **Award type:** 5
- **Project period:** 1977-09-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10176555

## Citation

> US National Institutes of Health, RePORTER application 10176555, Angiotensins, Prostaglandins-Adrenergic Interactions (5R01HL019134-46). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10176555. Licensed CC0.

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