Objective-The purpose of this study was to examine the interactive action of serum amyloid A (SAA), group IIA secretory phospholipase A 2 (sPLA 2 -IIA), and cholesteryl ester transfer protein (CETP) on HDL remodeling and cholesterol efflux during the acute phase (AP) response elicited in humans after cardiac surgery. Methods and Results-Plasma was collected from patients before (pre-AP), 24 hours after (AP-1 d), and 5 days after cardiac surgery (AP-5 d). SAA levels were increased 16-fold in AP-1 d samples. Key Words: SAA Ⅲ HDL Ⅲ CETP Ⅲ apoA-I Ⅲ inflammation I nflammation induces major changes in HDL levels and composition. Mediators of inflammation such as tumor necrosis factor (TNF)-␣ and interleukin (IL)-6 induce expression of serum amyloid A 1 and group IIA secretory phospholipase A 2 (sPLA 2 -IIA), 2 which dramatically alter HDL apolipoprotein content and levels, respectively. Acute phase SAA in the plasma is associated with HDL, where it can comprise the major apolipoprotein. 3 The increase in sPLA 2 -IIA activity results in hydrolysis of HDL surface phospholipids and a decrease in HDL particle size. 4 The plasma cholesteryl ester transfer protein (CETP) is an integral component of reverse cholesterol transport and regulates HDL cholesterol concentrations. By promoting the transfer of cholesteryl esters (CE) from HDL to apoB-containing lipoprotein particles, HDL-derived CE is taken up via the LDL receptor and cleared by the liver. 5 An additional result of CETP action is the generation of lipid-poor apoA-I, 6 a key acceptor in ATP-binding cassette transporter AI (ABCA1)-mediated lipid efflux. 7 The presence of SAA on HDL holds the potential to impact both the CE transfer and the apoA-I liberating ability of CETP. sPLA 2 -IIA could also impact the latter action of CETP as apoA-I was shown to dissociate more readily from CETP-remodeled reconstituted HDL after hydrolysis by bee venom phospholipase A 2 . 8 Given the centrality of inflammation in atherogenesis, there is a paucity of information regarding CETP function when acute phase HDL is the "substrate." In the present study, we used plasma from patients undergoing cardiac surgery with cardiopulmonary bypass as a "standardized" insult where the oxygenator membrane activates macrophages to produce cytokines. 9 We characterized the SAAcontaining acute phase (AP) HDL during the acute phase to define the polydisperse HDL "substrate" that CETP would encounter. We further investigated CETP function in the acute phase, particularly as it relates to the presence of SAA and sPLA 2 on AP HDL, with respect to its CE transfer and apoA-I liberating functions.Teleologically, the dramatic changes in HDL composition and metabolism during inflammation must serve a short-term purpose to allow the organism to survive a noxious assault. Acute tissue injury results in cell death with large quantities of cell membranes rich in phospholipids and cholesterol generated. Macrophages are mobilized to such sites, ingest these fragments, and acquire considerable lipid load. 10 We thus e...
Objective Although elevated plasma concentrations of serum amyloid A (SAA) are strongly associated with increased risk for atherosclerotic cardiovascular disease in humans, the role of SAA in the pathogenesis of lesion formation remains obscure. Our goal was to determine the impact of SAA deficiency on atherosclerosis in hypercholesterolemic mice. Approach and Results ApoE-/- mice, either wild type or deficient in both major acute phase SAA isoforms, SAA1.1 and SAA2.1 (SAAWT and SAAKO, respectively), were fed a normal rodent diet for 50 weeks. Female, but not male SAAKO mice had a modest increase (22%; p ≤ 0.05) in plasma cholesterol concentrations and a 53% increase in adipose mass compared to SAAWT mice that did not impact the plasma cytokine levels or the expression of adipose tissue inflammatory markers. SAA deficiency did not impact lipoprotein cholesterol distributions or plasma triglyceride concentrations in either male or female mice. Atherosclerotic lesion areas measured on the intimal surfaces of the arch, thoracic, and abdominal regions were not significantly different between SAAKO and SAAWT mice in either gender. To accelerate lesion formation, mice were fed a Western diet for 12 weeks. SAA deficiency had no effect on diet-induced alterations in plasma cholesterol, triglyceride or cytokine concentrationsn or on aortic atherosclerotic lesion areas in either male or female mice. In addition, SAA deficiency in male mice had no effect on lesion areas or macrophage accumulation in the aortic roots. Conclusions The absence of endogenous SAA1.1 and 2.1 does not impact atherosclerotic lipid deposition in apoE-/- mice fed either normal or Western diets.
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...
Serum amyloid A (SAA) is a family of acute-phase reactants. Plasma levels of human SAA1/SAA2 (mouse SAA1.1/2.1) can increase ≥1,000-fold during an acute-phase response. Mice, but not humans, express a third relatively understudied SAA isoform, SAA3. We investigated whether mouse SAA3 is an HDL-associated acute-phase SAA. Quantitative RT-PCR with isoform-specific primers indicated that SAA3 and SAA1.1/2.1 are induced similarly in livers (∼2,500-fold vs. ∼6,000-fold, respectively) and fat (∼400-fold vs. ∼100-fold, respectively) of lipopolysaccharide (LPS)-injected mice. In situ hybridization demonstrated that all three SAAs are produced by hepatocytes. All three SAA isoforms were detected in plasma of LPS-injected mice, although SAA3 levels were ∼20% of SAA1.1/2.1 levels. Fast protein LC analyses indicated that virtually all of SAA1.1/2.1 eluted with HDL, whereas ∼15% of SAA3 was lipid poor/free. After density gradient ultracentrifugation, isoelectric focusing demonstrated that ∼100% of plasma SAA1.1 was recovered in HDL compared with only ∼50% of SAA2.1 and ∼10% of SAA3. Thus, SAA3 appears to be more loosely associated with HDL, resulting in lipid-poor/free SAA3. We conclude that SAA3 is a major hepatic acute-phase SAA in mice that may produce systemic effects during inflammation.
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