# 15-PGDH as a better therapeutic target than aspirin in decreasing risk of intracranial aneurysm rupture in men and women equally

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2020 · $335,338

## Abstract

PROJECT SUMMARY / ABSTRACT
Small unruptured intracranial aneurysms (UIAs) (3–7 mm in diameter) have an average annual likelihood of
growth (≥1 mm) of 3% per year (range: 7–21% over 2–4 years of follow-up).1-11 Intracranial aneurysms (IA) that
enlarge have 12–24 times increased risk of rupture compared to those that do not.1-11 These data compelled
the AHA/ASA in their 2015 guidelines to strongly recommend surgical or endovascular treatment of UIAs that
enlarge,12 but the need for these expensive invasive procedures, which have associated morbidity and
mortality, could be limited if pharmaceutical treatments could be developed to prevent IA growth or rupture.
Based on data from a series of studies in humans and animals regarding UIAs, Aspirin has shown to
safe, inexpensive, and effective treatment to decrease IA growth and rupture.
But do women and men respond equally to ASA? The answer is NO. (A) Our animal study revealed that
there are sex-specific differences in the biologic response to ASA and the ability of ASA to reduce the risk of IA
rupture in mice.15 (B) We identified effects on expression of 15-PGDH as a potential cause of this phenomenon
and reversed these effects by activating this enzyme in female mice and inhibiting it in male mice.15 (C) The
finding of sex-specific responses to ASA in mice was confirmed in humans using data from ISUIA cohort, with
ASA being 20% more effective in reducing IA rupture in males than females.15 (D) Serum analysis of blood
collected from within human IA sacs showed significant elevation of 15-PGDH in males when compared to
females, confirming our findings in mice and adding more evidence of sex differential response to ASA and 15-
PGDH as potential explanation for this response.23
Our proposal seeks to test these primary hypotheses: (1) activation of 15-PGDH decreases the risk of IA
rupture by: a) decreasing the harmful expression of PGE2 and b) converting PGE2 to 15-keto PGE2 which acts
as an endogenous agonist of PPAR, which is known to decrease the risk of IA rupture; (2) the effect of 15-
keto PGE2 is cell-specific to smooth muscle cells and macrophages.
To test these hypotheses, we will perform these two specific aims:
Specific Aim 1: Test the hypothesis that activation of 15-PGDH decreases risk of UIA rupture equally in male
and female WT mice by (A) decreasing expression of PGE2 and (B) increasing 15-keto PGE2 which acts as an
endogenous agonist of PPAR which we showed decreases the risk of IA rupture. Specific Aim 2: Test the
hypothesis that the effect of 15-keto PGE2 (final byproduct of 15-PGDH which functionally acts as an
endogenous PPAR activator) primarily acts in smooth muscle cells (SMC) and macrophages (MΦ).

## Key facts

- **NIH application ID:** 9888455
- **Project number:** 5R01NS107293-02
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** David M Hasan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $335,338
- **Award type:** 5
- **Project period:** 2019-03-15 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9888455

## Citation

> US National Institutes of Health, RePORTER application 9888455, 15-PGDH as a better therapeutic target than aspirin in decreasing risk of intracranial aneurysm rupture in men and women equally (5R01NS107293-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9888455. Licensed CC0.

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