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Vascular Smooth Muscle Sirtuin‐1 Protects Against Aortic Dissection During Angiotensin II Infusion
Author(s) -
Fry Jessica,
Shiraishi Yasunaga,
Gao Yuan,
Weisbrod Robert,
Maziuk Brandon,
Weng Xiang,
Morgan Kathleen,
Cohen Richard,
Seta Francesca
Publication year - 2015
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.29.1_supplement.418.7
Subject(s) - angiotensin ii , vascular smooth muscle , aorta , aortic dissection , endocrinology , medicine , chemistry , thoracic aorta , sirtuin 1 , downregulation and upregulation , biochemistry , blood pressure , smooth muscle , gene
BACKGROUND Sirtuin‐1 (SIRT1), an NAD + ‐dependent deacetylase, is a key enzyme in the cellular response to metabolic, inflammatory, and oxidative stresses, however the role of SIRT1 in vascular smooth muscle (VSM) is unclear. OBJECTIVE To study the role of VSM SIRT1 in the physiological response of the aortic wall to angiotensin (Ang) II, a potent oxidant and inflammatory stimulus. METHODS We generated a VSM cell specific SIRT1 knock out mouse (SMKO) and infused AngII (1 mg/kg/d) by osmotic minipump and evaluated endpoints after 14 days. RESULTS SMKO mice had a drastically high mortality (70%) caused by aortic dissection, at both thoracic and abdominal sites, as early as 6 days after infusion of AngII, but not after equi‐pressor norepinephrine (10 mg/kg/d). Aortas from AngII‐treated SMKO mice had severely fragmented and disorganized elastic lamellae with frequent elastin breaks compared to WT/AngII and increased aortic stiffness measured ex vivo . Metalloproteinase (MMP)‐2 expression was increased in the aortas of both saline‐ and AngII‐treated SMKO mice compared to WT littermates. In gel zymography on whole aortic homogenates confirmed increased MMP activity in SMKO. Similarly, VSM cells isolated from SMKO aortas exhibited increased expression of MMP2, indicating a VSM rather than myeloid source. CONCLUSIONS The high incidence of aortic dissection in AngII‐treated SIRT1 SMKO mice (80%) indicate that endogenous SIRT1 in aortic smooth muscle is required to maintain the structural integrity of the aortic wall in response to oxidant and inflammatory stimuli. The SMKO infused with AngII is a novel model of aortic dissection. Research Support: NHLBI grant HL105287