Webb Nancy R, De Beer Maria C, Wroblewski Joanne M, Ji Ailing, Bailey William, Shridas Preetha, Charnigo Richard J, Noffsinger Victoria P, Witta Jassir, Howatt Deborah A, Balakrishnan Anju, Rateri Debra L, Daugherty Alan, De Beer Frederick C
From the Departments of Pharmacology Division of Nutritional Sciences (N.R.W.), Physiology (M.C.D.B.) and Internal Medicine (J.M.W., A.J., W.B., P.S., V.P.N., D.A.H., A.B., D.L.R., A.D., F.C.D.B.), and Saha Cardiovascular Research Center (N.R.W., M.C.D.B., J.M.W., A.J., P.S., V.P.N., D.A.H., A.B., D.L.R., A.D., F.C.D.B.), and Departments of Statistics and Biostatistics (R.J.C.), University of Kentucky, Lexington; and Foundation Gastroenterology, Nashua, NH (J.W.).
Arterioscler Thromb Vasc Biol. 2015 May;35(5):1156-65. doi: 10.1161/ATVBAHA.114.304776. Epub 2015 Mar 5.
Rupture of abdominal aortic aneurysm (AAA), a major cause of death in the aged population, is characterized by vascular inflammation and matrix degradation. Serum amyloid A (SAA), an acute-phase reactant linked to inflammation and matrix metalloproteinase induction, correlates with aortic dimensions before aneurysm formation in humans. We investigated whether SAA deficiency in mice affects AAA formation during angiotensin II (Ang II) infusion.
Plasma SAA increased ≈60-fold in apoE(-/-) mice 24 hours after intraperitoneal Ang II injection (100 μg/kg; n=4) and ≈15-fold after chronic 28-day Ang II infusion (1000 ng/kg per minute; n=9). AAA incidence and severity after 28-day Ang II infusion was significantly reduced in apoE(-/-) mice lacking both acute-phase SAA isoforms (SAAKO; n=20) compared with apoE(-/-) mice (SAAWT; n=20) as assessed by in vivo ultrasound and ex vivo morphometric analyses, despite a significant increase in systolic blood pressure in SAAKO mice compared with SAAWT mice after Ang II infusion. Atherosclerotic lesion area of the aortic arch was similar in SAAKO and SAAWT mice after 28-day Ang II infusion. Immunostaining detected SAA in AAA tissues of Ang II-infused SAAWT mice that colocalized with macrophages, elastin breaks, and enhanced matrix metalloproteinase activity. Matrix metalloproteinase-2 activity was significantly lower in aortas of SAAKO mice compared with SAAWT mice after 10-day Ang II infusion.
Lack of endogenous acute-phase SAA protects against experimental AAA through a mechanism that may involve reduced matrix metalloproteinase-2 activity.
腹主动脉瘤（AAA）破裂是老年人群死亡的主要原因，其特征为血管炎症和基质降解。血清淀粉样蛋白A（SAA）是一种与炎症及基质金属蛋白酶诱导相关的急性期反应物，与人类动脉瘤形成前的主动脉尺寸相关。我们研究了小鼠体内SAA缺乏是否会影响血管紧张素II（Ang II）输注期间AAA的形成。
腹膜内注射Ang II（100 μg/kg；n = 4）后24小时，载脂蛋白E基因敲除（apoE(-/-)）小鼠血浆SAA升高约60倍，慢性28天Ang II输注（1000 ng/kg每分钟；n = 9）后升高约15倍。通过体内超声和离体形态学分析评估，与apoE(-/-)小鼠（SAAWT；n = 20）相比，缺乏两种急性期SAA亚型的apoE(-/-)小鼠（SAAKO；n = 20）在28天Ang II输注后的AAA发生率和严重程度显著降低，尽管Ang II输注后SAAKO小鼠的收缩压与SAAWT小鼠相比显著升高。28天Ang II输注后，SAAKO和SAAWT小鼠主动脉弓的动脉粥样硬化病变面积相似。免疫染色在Ang II输注的SAAWT小鼠的AAA组织中检测到SAA，其与巨噬细胞、弹性蛋白断裂和增强的基质金属蛋白酶活性共定位。Ang II输注10天后，SAAKO小鼠主动脉中基质金属蛋白酶-2活性显著低于SAAWT小鼠。
内源性急性期SAA缺乏通过可能涉及降低基质金属蛋白酶-2活性的机制预防实验性AAA。
