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Intrinsic eNOS dysfunction causes vascular remodeling and abdominal aortic aneurysm
Author(s) -
Chalupsky Karel,
Nguyen Andrew,
Galis Zorina,
Jiang Helen,
Cai Hua “Linda”
Publication year - 2006
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.20.5.a1161-c
Subject(s) - enos , angiotensin ii , medicine , endocrinology , reactive oxygen species , chemistry , superoxide , abdominal aortic aneurysm , nitric oxide , nitric oxide synthase , blood pressure , biochemistry , aneurysm , enzyme , surgery
We recently showed that angiotensin II uncouples eNOS via NAD(P)H oxidase‐dependent production of hydrogen peroxide, resulting in accumulation of reactive oxygen species (PNAS, 2005). We sought to determine whether intrinsic eNOS dysfunction affects vascular function when challenged with angiotensin II. Mice deficient in GTP cyclohydrolase I (HPH‐1) have reduced tetrahydrobiopterin levels and markedly increased aortic superoxide production. The latter was abolished by L‐NAME, implicating uncoupling of eNOS. Aortic hydrogen peroxide production was also increased in HPH‐1 mice. WT (n=15) and HPH‐1 mice (n=12) were infused with angiotensin II (100 nmol/L) for 14 days. Mean blood pressure (MBP) was increased in both genotypes (WT: from 119±1 to 164±7; HPH‐1: from 117±1 to 160±3 mmHg) till day 10. MBP however started to drop since day 11 in HPH‐1 mice to 138±9 whereas in WT it continued to go up to 179±4 mmHg on day 14. 21% of HPH‐1 mice, both males and females, started to die suddenly. Immediate dissection and H&E staining revealed severe abdominal aortic aneurysm (AAA). None of the WT mice had AAA or sudden death during the 14‐day of angiotensin II infusion. Furthermore, zymography assay indicated that HPH‐1 mice had much higher aortic metalloproteinase 2 (MMP‐2) activities in response to angiotensin II, suggesting that hydrogen peroxide‐dependent pre‐activation of MMPs may underlie accelerated matrix degradation. These data for the first time demonstrated that intrinsic eNOS dysfunction can cause vascular remodeling, resulting in lethal aneurysm. This work is supported by American Heart Association and American Diabetes Association Grants 0435189N and 7‐04‐RA‐16, and NIH Grants HL077440 and HL081571 (all to H Cai).