Deficiency of Endogenous Acute-Phase Serum Amyloid A Protects apoE ^−/− Mice From Angiotensin II–Induced Abdominal Aortic Aneurysm Formation

Abstract

Objective-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. Approach and Results-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. Conclusions-Lack of endogenous acute-phase SAA protects against experimental AAA through a mechanism that may involve reduced matrix metalloproteinase-2 activity. Webb et al Serum Amyloid A Augments Abdominal Aortic Aneurysm 1157(MMPs) are thought to be intimately involved. 14 There is no proven medical therapy for AAA, with management of patients relying on routine monitoring of AAA size by ultrasound until surgical repair is implemented when the growth rate exceeds 10 mm/y or the diameter exceeds 55 mm.Although the physiological function(s) of SAA have not been clearly established, several studies link SAA with inflammatory processes implicated in AAA formation and progression, such as leukocyte chemotaxis, 15 induction of inflammatory cytokines, [16][17][18] and upregulation of genes involved in extracellular matrix remodeling, including transforming growth factor-β (TGF-β) 19 and MMP expression. 20-23To investigate the possibility that SAA plays a role in the initiation or progression of AAA, mice lacking both acute-phase SAA isoforms 24 were bred into a C57BL/6 background and then crossed with apoE −/− mice, which allowed us to take advantage of the widely used AAA model that involves infusing angiotensin II (Ang II) into hypercholesterolemic mice. Ang II-induced AAAs exhibit many features of human AAA, including medial degeneration, inflammation, thrombus formation, and rupture of the abdominal aorta. 25 Our results demonstrate that SAA augments MMP activity in the abdominal aorta and enhances AAA expansion in Ang II-infused apoE −/− mice. Materials and Meth...

High-density lipoprotein inhibits serum amyloid A–mediated reactive oxygen species generation and NLRP3 inflammasome activation

“…This finding has potential clinical implications, given the accumulating evidence that IL-1β and NLRP3 inflammasome activation play a critical role in the development of human and mouse AAA (27-32) and our previous report that SAA mediates AngII-induced AAA in mice (15). Circulating SAA is elevated in a number of chronic inflammatory diseases including obesity, type 2 diabetes, rheumatic diseases, cancer, and cardiovascular diseases where IL-1β is thought to play a pathological role.…”

“…During severe inflammation such as sepsis, SAA can account for as much as 2.5% of hepatic protein production, with serum SAA levels increasing >1000-fold (13), suggesting an important role for SAA in the immediate response to tissue injury and infection. On the other hand, chronically elevated SAA is associated with a wide variety of chronic pathological conditions (14,15). Although circulating SAA is thought to be primarily produced by hepatocytes, extra-hepatic synthesis of SAA has been reported in inflamed tissues (16,17).…”

“…Although circulating SAA is thought to be primarily produced by hepatocytes, extra-hepatic synthesis of SAA has been reported in inflamed tissues (16,17). Virtually all of circulating SAA is bound to the surface of high-density lipoprotein (HDL) (18 In a previous publication, we reported that SAA deficiency attenuates abdominal aortic aneurysm (AAA) formation in the mouse angiotension II (AngII) infusion model (15). In the current study, we determined that reduced AngII-induced AAA in SAA-deficient mice is accompanied by significant reductions in IL-1β, suggesting that inflammasome activation in AngII-infused mice is dependent on SAA.…”

“…We previously reported that lack of endogenous acute-phase SAA1.1 and SAA2.1 protects apoE -/-mice from angiotensin II (AngII)-induced AAA formation (15 1A). As a gainof-function approach, we overexpressed SAA1.1 in apoE -/-x SAA1.1/2.1-DKO mice using adenoassociated virus (AAV)-mediated gene transfer.…”

Impact of individual acute phase serum amyloid A isoforms on HDL metabolism in mice

“…An absence of SAA also did not affect atherosclerosis in an apoE-deficient mouse model (21). However, SAA was shown to enhance abdominal aortic aneurysm in an angII-dependent abdominal aortic aneurysm mouse model (22).…”