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Most endocrine disorders are chronic in nature, and thus even a minor effect to increase risk for cardiovascular disease can lead to a significant impact over prolonged duration. Although robust therapies exist for many endocrine disorders (eg suppression of excess hormone amounts, or replacement of hormone deficiencies), the therapies do not perfectly restore normal physiology. Thus, individuals with endocrine disorders are at potential increased cardiovascular disease risk, and maximizing strategies to reduce that risk are needed. This article reviews various endocrine conditions that can impact lipid levels and/or cardiovascular disease risk.

Background: Obesity increases the risk for human abdominal aortic aneurysms (AAAs) and enhances Ang II (angiotensin II)–induced AAA formation in C57BL/6J mice. Obesity is also associated with increases in perivascular fat that expresses proinflammatory markers including SAA (serum amyloid A). We previously reported that deficiency of SAA significantly reduces Ang II–induced inflammation and AAA in hyperlipidemic apoE-deficient mice. In this study. we investigated whether adipose tissue-derived SAA plays a role in Ang II–induced AAA in obese C57BL/6J mice. Methods: The development of AAA was compared between male C57BL/6J mice (wild type), C57BL/6J mice lacking SAA1.1, SAA2.1, and SAA3 (TKO); and TKO mice harboring a doxycycline-inducible, adipocyte-specific SAA1.1 transgene (TKO-Tg fat ; SAA expressed only in fat). All mice were fed an obesogenic diet and doxycycline to induce SAA transgene expression and infused with Ang II to induce AAA. Results: In response to Ang II infusion, SAA expression was significantly increased in perivascular fat of obese C57BL/6J mice. Maximal luminal diameters of the abdominal aorta were determined by ultrasound before and after Ang II infusion, which indicated a significant increase in aortic luminal diameters in wild type and TKO-TG fat mice but not in TKO mice. Adipocyte-specific SAA expression was associated with MMP (matrix metalloproteinase) activity and macrophage infiltration in abdominal aortas of Ang II–infused obese mice. Conclusions: We demonstrate for the first time that SAA deficiency protects obese C57BL/6J mice from Ang II–induced AAA. SAA expression only in adipocytes is sufficient to cause AAA in obese mice infused with Ang II.

Background In the US, serum thyroid-stimulating hormone (TSH) and thyroxine measurements are the fourth- and tenth-commonest laboratory tests ordered, respectively. Diagnosis of thyroid disorder requires clinical suspicion supported by laboratory values. However, in the setting of acute illness, both the clinical and laboratory pictures can be confounded. Objective To study clinical outcomes and derangement patterns of inpatient thyroid-function tests. Design This retrospective study was conducted at an academic center on admissions aged ≥18 years and TSH tests performed over a 1-year period. Admissions with active pregnancy and/or prior thyroid-related diagnosis were excluded. Main Outcomes Clinical outcomes were divided based on new diagnosis of thyroid-related disorder, newly prescribed thyroxine replacement, or antithyroid drugs/ endocrinology referrals, or both. In order to analyze the derangement patterns of abnormal TSH, only the results of the first test ordered were considered (as some admissions had multiple TSH tests ordered). Results A total of 7,204 admissions aged ≥18 years had TSH tests done. Of these, 1,912 were excluded. Of the 5,292 admissions with no prior thyroid disorder or active pregnancy, 183 (3.46%) were assigned a new diagnosis of thyroid-related disorder, 54 (1.02%) received treatment/referral, and 46 (0.87%) received both a new diagnosis and treatment/referral. Based on the TSH results (reference range 0.42-4.0 mIU/L) of the 5,292 admissions, 4,312 (81.5%) and 980 (18.5%) admissions were flagged normal and abnormal, respectively. Of the 980 admissions with one or more abnormal TSH results, 21 (2.14%) had first ordered TSH 10 mIU/L. Conclusion There is low value in testing inpatients for thyroid disorders, and testing comes at significant expense to the health-care system.

Objectives: Serum Amyloid A (SAA) is a family of proteins whose plasma levels increase > 1000-fold in acute inflammatory states such as sepsis. We and others have demonstrated that SAA plays a causal role in mouse models of atherosclerosis. However, SAA may not be a valid therapeutic target if it is needed for host defense in inflammation. Here, we investigated the role of SAA in sepsis using mice deficient in all three acute-phase SAA isoforms (TKO). Approach and results: SAA deficiency significantly increased mortality rates in three experimental sepsis models. Survival rates in TKO and wild-type (WT) mice were: 25% and 55% after cecal ligation and puncture (CLP; p=0.02; n=10 each strain/gender); 0% and 45% after cecal slurry injection (pProz, Dbp, Cxcl1, Cxcl2, Arg1 and Ackr1 . Gene ontology analysis revealed a significant enrichment of differentially expressed genes associated with chemokine production, chemokine and cytokine-mediated signaling, neutrophil chemotaxis and neutrophil migration in TKO lung tissues compared to WT tissues (p Conclusions: SAA protects mice against sepsis-induced mortality, potentially by protecting the lung from tissue damage. Thus, the risk of infection should be considered when targeting SAA to ameliorate atherosclerosis.

Several studies in the past have reported positive correlations between circulating Serum amyloid A (SAA) levels and obesity. However, based on limited number of studies involving appropriate mouse models, the role of SAA in the development of obesity and obesity-related metabolic consequences has not been established. Accordingly, herein, we have examined the role of SAA in the development of obesity and its associated metabolic complicationsin vivousing mice deficient for all three inducible forms of SAA: SAA1.1, SAA2.1 and SAA3 (TKO). Male and female mice were rendered obese by feeding a high fat, high sucrose diet with added cholesterol (HFHSC) and control mice were fed rodent chow diet. Here, we show that the deletion of SAA does not affect diet-induced obesity, hepatic lipid metabolism or adipose tissue inflammation. However, there was a modest effect on glucose metabolism. The results of this study confirm previous findings that SAA levels are elevated in adipose tissues as well as in the circulation in diet-induced obese mice. However, the three acute phase SAAs do not play a causative role in the development of obesity or obesity-associated adipose tissue inflammation and dyslipidemia.

Obesity increases the risk for abdominal aortic aneurysms (AAA) in humans, and enhances angiotensin II (AngII)-induced AAA formation in C57BL/6 mice. Obesity is also associated with increases in serum amyloid A (SAA). We previously reported that deficiency of SAA significantly reduces AngII-induced inflammation and AAA in apoE-deficient mice. In this study we investigated whether SAA plays a role in progression of an established AAA in obese C57BL/6 mice. Approach and Results: Male C57BL/6 mice were fed a high fat diet (60% kcal as fat) throughout the study. After 4 months of diet the mice were infused with angiotensin II (AngII) at 1000ng/kg/min until the end of the study. Ultrasound (US) was performed in all mice before and after 28 days of AngII infusion, and mice that had at least a 25% increase in the luminal diameter of the abdominal aorta were stratified by luminal diameter into 3 groups. Group 1 was killed to establish baseline AAA. Groups 2 and 3 continued to receive AngII for a further 8 weeks along with an antisense oligonucleotide (ASO) that suppresses all 3 acute phase SAA isoforms (SAA-ASO), or a control ASO (5 mg/kg/wk). US was repeated at study end to assess AAA progression. Plasma SAA at the end of the experiment was 89.2±83.2 mg/L in the control ASO group, and 18.6±0.7 mg/L in the SAA-ASO group (mean±SD , p=0.008). There was no impact of SAA suppression on body weight, body fat, or blood pressure. After the first 4 weeks of AngII infusion, the average luminal diameter in all mice was 1.81±0.40 mm (mean±SD). Mice that received the control ASO had continued aortic dilation (average luminal aortic diameter 2.06±0.42 mm), whereas the mice that received the SAA-ASO had a significant reduction in progression of aortic dilation (average luminal diameter 1.64±0.43 mm, p=0.0015 for interaction between time and group). Conclusions: We demonstrate for the first time that suppression of SAA protects obese C57BL/6 mice from progression of AngII-induced AAA. Suppression of SAA may be a therapeutic approach to limit AAA progression.

Purpose of review Acute phase serum amyloid A (SAA) is persistently elevated in chronic inflammatory conditions, and elevated levels predict cardiovascular risk in humans. More recently, murine studies have demonstrated that over-expression of SAA increases and deficiency/suppression of SAA attenuates atherosclerosis. Thus, beyond being a biomarker, SAA appears to play a causal role in atherogenesis. The purpose of this review is to summarize the data supporting SAA as a key player in atherosclerosis development. Recent findings A number of pro-inflammatory and pro-atherogenic activities have been ascribed to SAA. However, the literature is conflicted, as recombinant SAA, and/or lipid-free SAA, used in many of the earlier studies, do not reflect the activity of native human or murine SAA, which exists largely lipid-associated. Recent literatures demonstrate that SAA activates the NLRP3 inflammasome, alters vascular function, affects HDL function, and increases thrombosis. Importantly, SAA activity appears to be regulated by its lipid association, and HDL may serve to sequester and limit SAA activity. Summary SAA has many pro-inflammatory and pro-atherogenic activities, is clearly demonstrated to affect atherosclerosis development, and may be a candidate target for clinical trials in cardiovascular diseases.

BackgroundA major goal of the National Institutes of Health’s Clinical and Translational Science Award program is to facilitate clinical research and enhance the transition of basic to clinical research. As such, a number of Clinical and Translational Science Award centers have developed services to facilitate the conduct of clinical research, including support with fulfilling regulatory requirements.MethodsThe University of Kentucky sought to establish an institutional semi-independent monitoring committee to provide oversight for clinical research studies per National Institutes of Health requirements and recommendations. Our semi-independent monitoring committee was initiated in 2010.ResultsSince the inception of our semi-independent monitoring committee we have restructured its operations and protocols to improve efficiency. This article discusses our experiences with semi-independent monitoring committee creation and growth.ConclusionThis article summarizes our experience in creating and maturing an institutional data monitoring committee.

Objective This guideline will provide the practicing endocrinologist with an approach to the assessment and treatment of dyslipidemia in patients with endocrine diseases, with the objective of preventing cardiovascular (CV) events and triglyceride-induced pancreatitis. The guideline reviews data on dyslipidemia and atherosclerotic cardiovascular disease (ASCVD) risk in patients with endocrine disorders and discusses the evidence for the correction of dyslipidemia by treatment of the endocrine disease. The guideline also addresses whether treatment of the endocrine disease reduces ASCVD risk. Conclusion This guideline focuses on lipid and lipoprotein abnormalities associated with endocrine diseases, including diabetes mellitus, and whether treatment of the endocrine disorder improves not only the lipid abnormalities, but also CV outcomes. Based on the available evidence, recommendations are made for the assessment and management of dyslipidemia in patients with endocrine diseases.

Objective— SAA (serum amyloid A) is a family of acute-phase reactants that have proinflammatory and proatherogenic activities. SAA is more lipophilic than apoA-I (apolipoprotein A-I), and during an acute-phase response, Approach and Results— Delipidated human SAA was incubated with SAA-free human lipoproteins; then, samples were reisolated by fast protein liquid chromatography, and SAA analyzed by ELISA and immunoblot. Both in vitro and in vivo, we show that SAA associates with any lipoprotein and does not remain in a lipid-free form. Although SAA is preferentially found on high-density lipoprotein, it can exchange between lipoproteins. In the presence of CETP (cholesterol ester transfer protein), there is greater exchange of SAA between lipoproteins. Subjects with diabetes mellitus, but not those with metabolic syndrome, showed altered SAA lipoprotein distribution postprandially. Proteoglycan-mediated lipoprotein retention is thought to be an underlying mechanism for atherosclerosis development. SAA has a proteoglycan-binding domain. Lipoproteins containing SAA had increased proteoglycan binding compared with SAA-free lipoproteins. Conclusions— Thus, SAA is an exchangeable apolipoprotein and increases apoB-containing lipoproteins’ proteoglycan binding. We and others have previously reported the presence of SAA on low-density lipoprotein in individuals with obesity, diabetes mellitus, and metabolic syndrome. We propose that the presence of SAA on apoB-containing lipoproteins may contribute to cardiovascular disease development in these populations.

Vascular biglycan contributes to atherosclerosis development and increased biglycan expression correlates with increased atherosclerosis. However, mice deficient in biglycan have either no reduction in atherosclerosis or an unexpected increase in atherosclerosis. Biglycan deficient mice have systemically elevated TGF-β, likely due to lack of sequestration of TGF-β in the extracellular matrix. The purpose of this study was to determine if prevention of TGF-β elevations in biglycan deficient mice affected atherosclerosis development.Biglycan deficient mice were crossed to Ldlr deficient mice. Diabetes was induced via streptozotocin and all mice were fed a high cholesterol diet. Diabetic biglycan wild type and biglycan deficient Ldlr deficient mice were injected with the TGF-β neutralizing antibody 1D11 or the irrelevant control antibody 13C4.Biglycan deficient mice had significantly elevated plasma TGF-β levels, which was further increased by diabetes, and significantly increased atherosclerosis. There was a significant correlation between TGF-β concentrations and atherosclerosis. However, despite nearly complete suppression of plasma TGF-β levels in mice treated with the TGF-β neutralizing antibody 1D11, there was no significant difference in atherosclerosis between mice with elevated TGF-β levels and mice with suppressed TGF-β levels.The increased atherosclerosis in biglycan deficient mice does not appear to be due to elevations in TGF-β.

Animal studies demonstrate that hyperlipidemia and renal lipid accumulation contribute to the pathogenesis of diabetic nephropathy (DN). We previously demonstrated that renal lipoproteins colocalize with biglycan, a renal proteoglycan. The purpose of this study was to determine whether prevention of renal lipid (apoB) accumulation attenuates DN. Biglycan-deficient and biglycan wild-type Ldlr−/− mice were made diabetic via streptozotocin and fed a high cholesterol diet. As biglycan deficiency is associated with elevated transforming growth factor-β (TGF-β), in some experiments mice were injected with either the TGF-β-neutralizing antibody, 1D11, or with 13C4, an irrelevant control antibody. Biglycan deficiency had no significant effect on renal apoB accumulation, but led to modest attenuation of DN with ∼30% reduction in albuminuria; however, biglycan deficiency caused a striking elevation in TGF-β. Use of 1D11 led to sustained suppression of TGF-β for approximately 8 weeks at a time. The 1D11 treatment caused decreased renal apoB accumulation, decreased albuminuria, decreased renal hypertrophy, and improved survival, compared with the 13C4 treatment. Thus, prevention of renal apoB accumulation is protective against development of DN. Furthermore, this study demonstrates that prevention of renal apoB accumulation is a mechanism by which TGF-β inhibition is nephroprotective.

Disruption of the circadian system caused by disordered exposure to light is pervasive in modern society and increases the risk of cardiovascular disease. The mechanisms by which this happens are largely unknown. ApolipoproteinE-deficient (ApoE−/−) mice are studied commonly to elucidate mechanisms of atherosclerosis. In this study, we determined the effects of light-induced circadian disruption on atherosclerosis in ApoE−/− mice. We first characterized circadian rhythms of behavior, light responsiveness, and molecular timekeeping in tissues from ApoE−/− mice that were indistinguishable from rhythms in ApoE+/+ mice. These data showed that ApoE−/− mice had no inherent circadian disruption and therefore were an appropriate model for our study. We next induced severe disruption of circadian rhythms by exposing ApoE−/− mice to constant light for 12 weeks. Constant light exposure exacerbated atherosclerosis in male, but not female, ApoE−/− mice. Male ApoE−/− mice exposed to constant light had increased serum cholesterol concentrations due to increased VLDL/LDL fractions. Taken together, these data suggest that ApoE−/− mice are an appropriate model for studying light-induced circadian disruption and that exacerbated dyslipidemia may mediate atherosclerotic lesion formation caused by constant light exposure.

One in 4 Americans >40 years of age takes a statin to reduce the risk of myocardial infarction, ischemic stroke, and other complications of atherosclerotic disease. The most effective statins produce a mean reduction in low-density lipoprotein cholesterol of 55% to 60% at the maximum dosage, and 6 of the 7 marketed statins are available in generic form, which makes them affordable for most patients. Primarily using data from randomized controlled trials, supplemented with observational data where necessary, this scientific statement provides a comprehensive review of statin safety and tolerability. The review covers the general patient population, as well as demographic subgroups, including the elderly, children, pregnant women, East Asians, and patients with specific conditions such as chronic disease of the kidney and liver, human immunodeficiency viral infection, and organ transplants. The risk of statin-induced serious muscle injury, including rhabdomyolysis, is

Transgender patients may seek hormone therapy to induce physical changes to simulate their expressed or experienced gender. However, many providers are uncomfortable prescribing transgender hormones due to fears over safety. The goal of this study was to determine if transgender hormone therapy with estrogen and spironolactone for male-to-female (MtF) patients or with testosterone for female-to-male (FtM) patients had adverse anthropomorphic or metabolic effects.This retrospective chart review study analyzed changes over time for 33 MtF and 19 FtM endocrine clinic patients at an academic endocrine practice with follow-up for up to 18 months after hormone initiation.Compared to baseline labs obtained prior to the initiation of hormone therapy, significant changes for the MtF cohort included an increase in high-density lipoprotein (HDL) and decrease in creatinine; however, triglycerides did not show a statistically significant change. In the FtM cohort, there were significant increases in body mass index, creatinine, hemoglobin, and hematocrit. Although statistically significant, these changes were minimal for both cohorts.In our practice, hormone therapy was found to be safe in this retrospective study.

Purpose: There are currently no recommendations regarding the starting doses of hormone therapy for individuals with gender dysphoria. The purpose of this study was to assess the hormone dose needed to achieve target hormone levels in transgender men and transgender women, and whether body mass index (BMI) affects these doses. Methods: A retrospective chart review of subjects seeking gender-affirming hormone therapy was performed. Height, weight, hormone doses, and serum hormone levels were collected from charts. Data were analyzed for a correlation between BMI and effective hormone dosing (dose that achieved hormone levels in the target range). Results: Charts from 319 subjects were reviewed; however, only 84 transgender women and 71 transgender men had serum hormone levels available and only 40 transgender women and 54 transgender men had plasma hormone levels in the target range (normal range for affirmed gender). For transgender women, there was a significant negative correlation between BMI and effective estradiol dose (r = −0.337, p = 0.04). For transgender men, there was a positive correlation between BMI and effective testosterone dose (r = 0.409, p = 0.002). Conclusion: Increased BMI was associated with lower estrogen dose requirements in transgender women. In transgender men, an increase in BMI was associated with increased testosterone dose requirements. These results suggest that BMI may influence effective gender-affirming hormone dosing; however, further studies are needed to examine its utility in determining the initial hormone dose.

Serum amyloid A (SAA) is a family of acute phase reactants that are elevated in chronic inflammatory conditions such as obesity and diabetes. SAA promotes atherosclerosis in mice. Although SAA is generally thought to be exclusively an HDL apolipoprotein, we and others have detected SAA on apoB-containing lipoproteins in obese/diabetic mice and humans. The goal of this study was to investigate mechanisms underlying SAA exchange between lipoprotein fractions. Obese humans with or without metabolic syndrome or type 2 diabetes were recruited. Plasma samples were collected fasting and hourly for 8h after consumption of a high fat drink. Whereas SAA was found predominantly on HDL in fasting samples, in diabetic subjects SAA shifted from HDL to VLDL and LDL in post prandial samples. Postprandial LDL and VLDL containing SAA had increased proteoglycan binding compared to fasting LDL and VLDL from the same subject. We previously reported that HDLs remodeled by CETP release lipid-free SAA. To determine if CETP facilitates SAA exchange between particles, HDL-containing SAA was incubated with SAA-free VLDL in the presence of increasing amounts of CETP. Even in the absence of CETP, 16±3% of HDL-associated SAA shifted to VLDL; in samples with CETP, 19-28% of total SAA was found on VLDL and up to 17% was lipid-poor/lipid-free. To investigate whether CETP promotes SAA exchange in vivo, SAA-deficient mice that lack CETP were injected with HDL containing SAA and then bled at 1, 3, 6 and 24 hours. Essentially all SAA was found on HDL at each time point. In contrast, in SAA-deficient mice expressing CETP by adenoviral vector, approximately 50% and 20% of SAA was associated with the VLDL and LDL fractions, respectively, 1h after injection of HDL-containing SAA. Thus, increased CETP activity in diabetes may promote the transfer of SAA from HDL to apoB-containing lipoproteins, leading to increased retention in the vasculature.

The availability of new techniques and technologies to answer important medical questions is accelerating at a breathtaking pace. In response to these exciting new opportunities, clinical departments, in general, and departments of medicine, in particular, have broadened their research portfolios. Organization of the traditional structures of clinical departments, research infrastructure, training programs, and rewards for faculty has only begun to catalyze emerging research areas such as artificial intelligence, bioinformatics, bioengineering, cell and tissue engineering, cost effectiveness, health services, implementation science, integrative epidemiology, medical informatics, nanomedicine, and quality improvement. Success in these emerging areas of research requires interdisciplinary collaboration on a much larger scale than in the past. The effectiveness of efforts to recruit, develop, mentor, and promote faculty in these exciting areas will be critical to the success of departmental and institutional research programs. We describe examples of initiatives from our 5 departments of medicine designed to develop and promote faculty conducting research in emerging interdisciplinary areas. We focus on core resources, training, organizational structures, and recognition and promotion. Faculty have a compelling opportunity and obligation to pursue emerging research areas that have the potential to further improve the prevention, diagnosis, and treatment of disease. As departments prepare to meet this exciting opportunity in the future, the lessons learned must inform investments in faculty development. Although many of the strategies outlined herein could and should expand beyond any individual department, departments of medicine have a distinct obligation and opportunity to lead this effort.

ANOVA = analysis of variance; BMI = body mass index; HbA1c = glycated hemoglobin; TDD = total daily dose; VAMC = Veterans Affairs Medical Center.

Serum amyloid A (SAA) has a number of proatherogenic effects including induction of vascular proteoglycans. Chronically elevated SAA was recently shown to increase atherosclerosis in mice. The purpose of this study was to determine whether a brief increase in SAA similarly increased atherosclerosis in a murine model. The recombination activating gene 1-deficient (rag1(-/-)) × apolipoprotein E-deficient (apoe(-/-)) and apoe(-/-) male mice were injected, multiple times or just once respectively, with an adenoviral vector encoding human SAA1 (ad-SAA); the injected mice and controls were maintained on chow for 12-16 weeks. Mice receiving multiple injections of ad-SAA, in which SAA elevation was sustained, had increased atherosclerosis compared with controls. Strikingly, mice receiving only a single injection of ad-SAA, in which SAA was only briefly elevated, also had increased atherosclerosis compared with controls. Using in vitro studies, we demonstrate that SAA treatment leads to increased LDL retention, and that prevention of transforming growth factor beta (TGF-β) signaling prevents SAA-induced increases in LDL retention and SAA-induced increases in vascular biglycan content. We propose that SAA increases atherosclerosis development via induction of TGF-β, increased vascular biglycan content, and increased LDL retention. These data suggest that even short-term inflammation with concomitant increase in SAA may increase the risk of developing CVD.

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.

Background and aims Serum amyloid A (SAA) predicts cardiovascular events. Overexpression of SAA increases atherosclerosis development; however, deficiency of two of the murine acute phase isoforms, SAA1.1 and SAA2.1, has no effect on atherosclerosis. SAA3 is a pseudogene in humans, but is an expressed acute phase isoform in mice. The goal of this study was to determine if SAA3 affects atherosclerosis in mice. Methods ApoE-/- mice were used as the model for all studies. SAA3 was overexpressed by an adeno-associated virus or suppressed using an anti-sense oligonucleotide approach. Results Over-expression of SAA3 led to a 4-fold increase in atherosclerosis lesion area compared to control mice (p = 0.01). Suppression of SAA3 decreased atherosclerosis in mice genetically deficient in SAA1.1 and SAA2.1 (p Conclusions SAA3 augments atherosclerosis in mice. Our results resolve a previous paradox in the literature and support extensive epidemiological data that SAA is pro-atherogenic.

Serum Amyloid A (SAA) is traditionally thought to be only found with HDL; however, recently several groups have found that SAA is found on apoB-containing lipoproteins (LDL and VLDL) under some circumstances. The goal of this study was to determine the relative lipoprotein association of SAA. Native human acute phase SAA was isolated from acute phase plasma collected from patients undergoing cardiovascular bypass surgery; the SAA was purified and delipidated. Plasma was collected from a group of healthy, non-obese humans with low levels of SAA (< 2 mg/L) and lipoproteins (VLDL, LDL and HDL) were isolated by density gradient ultracentrifugation. The delipidated SAA (at 2 concentrations) was incubated in vitro with the various lipoprotein preparations then samples were re-isolated by fast protein liquid chromatography and SAA was analyzed by ELISA and immunoblot. When SAA was incubated with any single lipoprotein all of the SAA was found associated with that lipoprotein and none remained in a lipid-free form. When SAA was incubated with a mixture of VLDL, LDL and HDL (based on equal protein and corresponding to concentrations in plasma) a majority of SAA (50-60%) was found on HDL with the remaining SAA found on VLDL and LDL. When SAA first complexed to HDL was added to a mixture of SAA-free LDL and VLDL the majority of SAA remained with the HDL (76-86%) but 5-10% of the SAA was found on each of LDL and VLDL. When SAA first complexed to either apoB-containing lipoprotein was then added to a mixture of HDL and the other apoB-containing lipoprotein most SAA moved to HDL (55-70%) but the remainder was found on the apoB-containing particles. Thus, SAA can move between lipoprotein particles in vitro. To determine if the presence of SAA on apoB-containing lipoproteins had a functional effect we evaluated lipoprotein-proteoglycan binding affinity. Proteoglycan mediated lipoprotein retention in the vessel wall is thought to be one of the key steps in initiation of atherosclerosis. Compared to SAA-free LDL or VLDL, the presence of SAA on apoB-containing lipoproteins caused increased proteoglycan binding affinity. Thus, SAA is not simply an HDL lipoprotein, but SAA can move between lipoprotein particles, and the presence of SAA on apoB particles may increase their atherogenicity.