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Gender Differential Upregulation of 15‐Hydroxyprostaglandin Dehydrogenase Associates with Aspirin Decreasing Intracranial Aneurysm (IA) Rupture in Mice
Author(s) -
Lu Yongjun,
Ishii Daizo,
Hasan David M.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.09168
Subject(s) - aspirin , aneurysm , incidence (geometry) , medicine , lumen (anatomy) , basal (medicine) , endocrinology , cardiology , gastroenterology , surgery , physics , insulin , optics
Previously we showed 1) that aspirin decreased the risk of IA rupture significantly more in male than in female in the International Study of Unruptured Intracranial Aneurysms (ISUIA) and 2) the presence of sex‐differential plasma level of 15‐hydroxyprostaglandin dehydrogenase (15‐PGDH) in the lumen of human IAs. These observations were confirmed in our animal experiments using established mouse model of IAs. However, the aspirin dose used in these experiments was high (25 mg/kg/d). In the present study, we used a lower dose of aspirin 5 mg/kg/d (comparable to 325 mg for human) in our mouse‐model experiments to examine the protective effect of aspirin at lower doses and to test whether such sex differential response still exists in response to lower dose of aspirin. Aneurysms were induced with hypertension using Angiotensin II infusion (1000ng/kg/min for 21 days) and elastase (35m Units, single injection into mice basal cisterns). When grouping males and females together (n=30), aspirin decreased significantly the incidence of aneurysm when compared to control (60% vs 87%, p=0.0164), and the incidence of aneurysm rupture (43% vs 68%, p=0.0480). When analyzing the incidence of aneurysm rupture by gender (n=15), the incidence of aneurysm formation was significantly lower in male versus female mice on aspirin (40% vs 80%, p=0.0302), and the incidence of aneurysm rupture was lower in male mice (33% vs 53%, p=0.2311). qPCR analysis from individual mouse cerebral arteries showed significantly higher wall tissue of 15‐PGDH mRNA in male than in female mice at baseline (before administering aspirin) (1.69±0.12 vs 1.10±0.14, p=0.027). Administering aspirin upregulated this expression and maintained the sex difference (2.37±0.30 vs 1.25±0.12, p=0.012). These observations further validate the previous findings that aspirin protect against IA rupture significantly more in males than in females, potentially via 15‐PGDH pathway, which may provide a new promising therapeutic target for decreasing risk of aneurysm ruptures. Support or Funding Information NIH, 1R01NS107293‐01A1