Serum Levels of Lipoprotein Lipase Are Increased in Patients with Inflammatory Bowel Disease.

Disruption of the lipid profile is commonly found in patients with inflammatory bowel disease (IBD). Lipoprotein lipase (LPL) is a key molecule involved in triglyceride metabolism that plays a significant role in the progression of atherosclerosis. In this study, our aim was to study whether serum LPL levels are different in IBD patients and controls and whether IBD features are related to LPL. This was a cross-sectional study that encompassed 405 individuals; 197 IBD patients with a median disease duration of 12 years and 208 age- and sex-matched controls. LPL levels and a complete lipid profile were assessed in all individuals. A multivariable analysis was performed to determine whether LPL serum levels were altered in IBD and to study their relationship with IBD characteristics. After the fully multivariable analysis, including cardiovascular risk factors and the changes in lipid profile that the disease causes itself, patients with IBD showed significantly higher levels of circulating LPL (beta coefficient 196 (95% confidence interval from 113 to 259) ng/mL, p < 0.001). LPL serum levels did not differ between Crohn's disease and ulcerative colitis. However, serum C-reactive protein levels, disease duration, and the presence of an ileocolonic Crohn's disease phenotype were found to be significantly and independently positively related to LPL. In contrast, LPL was not associated with subclinical carotid atherosclerosis. In conclusion, serum LPL levels were independently upregulated in patients with IBD. Inflammatory markers, disease duration and disease phenotype were responsible for this upregulation.

Disease activity in patients with rheumatoid arthritis increases serum levels of apolipoprotein C-III.

OBJECTIVES: Rheumatoid arthritis (RA) has been unequivocally associated with an increased burden of accelerated atherosclerosis, which, at least in part, is a consequence of the inflammation present in the disease. Apolipoprotein C-III (ApoC3) is a key molecule in triglycerides metabolism that has been linked to cardiovascular (CV) disease. Our objective was to study how ApoC3 is related to the characteristics of RA, paying special attention to its relationship with the inflammatory activity of the disease. METHODS: Cross-sectional study that included 430 patients with RA. In these patients, data related to the disease, classic CV risk factors, complete lipid profile, and serum ApoC3 levels were evaluated. A multivariable regression analysis was performed to study the relationship of the characteristics of RA with ApoC3. RESULTS: Abdominal circumference, obesity, type 2 diabetes, and circulating triglycerides were significantly associated with higher ApoC3 serum levels. Furthermore, C-reactive protein and erythrocyte sedimentation rate, as well as the disease activity score -DAS28- were significantly related to a higher circulating ApoC3 after multivariable analysis. Patients included in the moderate or high disease activity groups had higher ApoC3 serum levels compared to those in remission (beta coefficient 1.28 [95% confidence interval 0.16-2.39] mg/dl, p=0.025) when adjusting for confounders. The use of prednisone, disease-modifying anti-rheumatic drugs and anti-tumour necrosis factor therapies was associated with lower values of ApoC3. CONCLUSIONS: The activity of the disease in patients with RA is independently associated with higher serum levels of ApoC3.

Key Molecules of Triglycerides Pathway Metabolism Are Disturbed in Patients With Systemic Lupus Erythematosus.

Background: Elevated triglycerides or triglyceride-rich lipoproteins are an additional cause of cardiovascular (CV) disease. Given that patients with systemic lupus erythematosus (SLE) have a high prevalence of premature CV disease and show an altered lipid profile, our objective was to study whether three molecules that play a central role in the triglyceride metabolism: apolipoprotein C-III (ApoC3), angiopoietin-like protein 4 (ANGPLT4), and lipoprotein lipase (LPL) differ between SLE patients and controls, and how they are related to disease characteristics, including disease damage. Methods: Cross-sectional study that included 347 women, 185 of them diagnosed with SLE and 162 age-matched controls. ANGPTL4, ApoC3 and LPL, and standard lipid profiles were analyzed in SLE patients and controls. A multivariable analysis was performed to assess whether ANGPTL4, ApoC3 and LPL molecules differ between patients and controls and to study their relationship with SLE disease damage. Results: After fully multivariable analysis that included classic CV risk factors, and the modifications that the disease itself produces over the lipid profile, it was found that ApoC3 was significantly lower (beta coef. -1.2 [95%CI -1.6- -0.8) mg/dl, <0.001), and ANGPTL4 (beta coef. 63 [95%CI 35-90] ng/ml, <0.001) and LPL (beta coef. 79 [95%CI 30-128] ng/ml, p=0.002) significantly higher in patients with SLE compared to controls. Disease damage score was significantly and independently associated with higher serum levels of LPL (beta coef. 23 [95%CI 10-35] ng/ml, p=0.001). Mediation analysis suggested that the relationship between disease damage and LPL was direct and not mediated by ApoC3 or ANGPLT4. Conclusion: The ApoC3, ANGPLT4 and LPL axis is disrupted in patients with SLE. Disease damage explains this disturbance.

Apolipoprotein C-III is linked to the insulin resistance and beta-cell dysfunction that are present in rheumatoid arthritis.

BACKGROUND: Insulin resistance and beta-cell dysfunction are manifestations of rheumatoid arthritis (RA). Apolipoprotein C-III (ApoC3) has been associated with such insulin resistance and beta-cell dysfunction in the general population. Our purpose was to study whether ApoC3 is also related to the insulin resistance and beta-cell dysfunction that are present in patients with RA. METHODS: Three hundred thirty-eight non-diabetic patients with RA who had a glycemia lower than 110 mg/dl were recruited. Insulin, C-peptide, and ApoC3 were assessed. Insulin resistance and beta-cell function were calculated using the Homeostasis Model Assessment (HOMA2) indices. A multivariable regression analysis was performed to study the relationship of ApoC3 with those molecules and indices adjusting for classic factors associated with insulin resistance that included glucocorticoids. RESULTS: ApoC3 was related to significant higher levels of circulating insulin (beta coef. 0.37 [95%CI 0.01-0.73] µU/ml, p = 0.044) and C-peptide (beta coef. 0.13 [95%CI 0.05-0.22] ng/ml, p = 0.003), and higher insulin resistance -HOMA2-IR- (beta coef. 0.05 [95%CI 0.00-0.09], p = 0.041) and beta-cell dysfunction -HOMA2-%B- (beta coef. 2.94 [95%CI 0.07-5.80], p = 0.044) indices. This was found after a fully multivariable analysis that included, among others, prednisone intake and the classic factors associated with carbohydrate metabolism such as triglycerides, waist circumference, and obesity. CONCLUSION: ApoC3, insulin resistance, and beta-cell dysfunction are independently associated in patients RA.

Apolipoprotein C3 Is Downregulated in Patients With Inflammatory Bowel Disease.

INTRODUCTION: Inflammatory bowel disease (IBD) has been associated with an abnormal lipid profile. Apolipoprotein C-III (ApoC3) is a key molecule of triglyceride metabolism that is known to be related to inflammation and cardiovascular disease. In this study, we aim to study whether ApoC3 serum levels differ between patients with IBD and controls and whether the hypothetical disturbance of ApoC3 can be explained by IBD characteristics. METHODS: This is a cross-sectional study that included 405 individuals, 197 patients with IBD and 208 age-matched and sex-matched controls. ApoC3 and standard lipid profiles were assessed in patients and controls. A multivariable analysis was performed to analyze whether ApoC3 serum levels were altered in IBD and to study their relationship to IBD characteristics. RESULTS: After fully multivariable analysis including cardiovascular risk factors, use of statins, and changes in lipid profile caused by the disease itself, patients with IBD showed significant lower serum levels of ApoC3 (beta coef. -1.6 [95% confidence interval -2.5 to -0.7] mg/dL, P = 0.001). Despite this, inflammatory markers, disease phenotypes, or disease activity of IBD was not found to be responsible for this downregulation. DISCUSSION: Apolipoprotein C3 is downregulated in patients with IBD.

The angiopoietin-like protein 4, apolipoprotein C3, and lipoprotein lipase axis is disrupted in patients with rheumatoid arthritis.

BACKGROUND: Modulators of triglyceride metabolism include lipoprotein lipase (LPL), angiopoietin-like protein 4 (ANGPTL4), and apolipoprotein C-3 (ApoC3). There is evidence on the influence of this triangle of molecules on an increased risk of atherosclerotic cardiovascular disease (CV) in the general population. Patients with rheumatoid arthritis (RA) present changes in lipid profiles and accelerated CV disease. In the present study, we set out to study whether the ANGPTL4, ApoC3, and LPL axis differs in subjects with RA compared to controls. In a further step, we investigated the relationship of this axis with subclinical atherosclerosis in patients with RA. METHODS: Cross-sectional study that included 569 individuals, 323 patients with RA and 246 age-matched controls. ANGPTL4, ApoC3 and LPL, and standard lipid profiles were analyzed in patients and controls. Carotid intima-media thickness (cIMT) and carotid plaques were assessed in RA patients. A multivariable analysis was performed to assess whether the ANGPTL4, ApoC3, and LPL axis was altered in RA and to study its relationship with RA dyslipidemia and subclinical carotid atherosclerosis. RESULTS: Most lipid profile molecules did not differ between patients and controls. Despite this, and after fully multivariable analysis including CV risk factors, use of statins, and changes in the lipid profile caused by the disease itself, patients with RA showed higher serum levels of ANGPTL4 (beta coef. 295 [95% CI 213-376] ng/ml, p<0.001) and ApoC3 (beta coef. 2.9 [95% CI 1.7-4.0] mg/dl, p<0.001), but lower circulating LPL (beta coef. -174 [95% CI -213 to -135] ng/ml, p<0.001). ANGPTL4 serum levels were positively and independently associated with a higher cIMT in patients with RA after fully multivariable adjustment. CONCLUSION: The axis consisting in ANGPTL4, ApoC3, and LPL is disrupted in patients with RA. ANGPTL4 serum levels are positively and independently associated with a higher cIMT in RA patients.

Amylin serum levels are upregulated in patients with systemic lupus erythematosus.

OBJECTIVES: Amylin is a pancreatic hormone that participates in glucose homeostasis. We aimed to investigate how serum amylin levels are expressed in patients with systemic lupus erythematosus (SLE) compared to matched controls, and their possible relationship to disease-related characteristics, such as activity or damage. METHODS: 144 SLE patients and 96 non-diabetic sex- (female 96% vs. 91%, p=0.43) and age-matched controls (49±11 vs. 51±8 years, p=0.09) were included. Amylin, insulin and C-peptide serum levels, as well as insulin resistance indexes were assessed in both groups. Multivariable regression analysis was performed to compare amylin between groups and to explore its interrelations with SLE features. The analyses were adjusted for glucocorticoids intake and for insulin resistance classic risk factors. RESULTS: Patients with SLE exhibited significant higher serum levels of amylin when compared to controls after multivariable analysis (beta coef. 1.56 [95%CI 1.01-2.11], p=0.000). Moreover, SLE patients not on prednisone (beat coef. 1.54 [95%CI 0.98-2.10] ng/ml, p=0.000) and those on prednisone (beta coef. 1.51 [95%CI 0.96-2.07] ng/ml, p=0.000) disclosed higher amylin serum levels compared to controls in the fully multivariable analysis. Hyperamylinaemia in SLE patients remained significant even adjusting for differences in the insulin resistance and beta cell production rates between patients and controls. The damage produced by the disease and its severity were independently and positively associated with amylin serum levels. CONCLUSIOINS: Amylin is upregulated in SLE patients compared to controls, regardless of the insulin resistance that SLE may present. The damage produced by the disease and its severity independently explains this upregulation.

HDL cholesterol efflux capacity and lipid profile in patients with systemic sclerosis.

OBJECTIVE: It is well established that patients with systemic sclerosis (SSc) have a disrupted lipid profile and an increased cardiovascular risk. Cholesterol efflux capacity (CEC), the ability of high-density lipoprotein (HDL)-cholesterol to accept cholesterol from macrophages, has been linked to cardiovascular events. The aim of this study was to establish whether CEC and lipid profile were impaired in SSc patients with respect to controls and whether these changes were associated with disease-related data. METHODS: Cross-sectional study encompassed 188 individuals: 73 SSc patients and 115 controls. CEC, using an in vitro assay, and lipoprotein serum concentrations were assessed in patients and controls. A multivariable analysis was performed to study the differences in CEC between patients and controls, and if SSc-related data could explain such differences. RESULTS: The multivariable analysis adjusted for demographic characteristics, cardiovascular risk factors, and lipid-related molecules showed that total cholesterol (beta coefficient: - 22 [95%CI - 37 to - 7], p = 0.004), triglycerides (beta coefficient: 24 [95%CI 2-47], p = 0.033), lipoprotein A (beta coefficient: 22 [95%CI 2-43], p = 0.033), and CEC (beta coefficient: - 6 [95%CI - 10 to - 2]%,p = 0.002) were significantly different between patients and controls. Skin thickness, as assessed by modified Rodnan skin score, was independently associated with a lower CEC (beta coefficient: - 0.21 [95%CI - 0.37 to - 0.05]%, p = 0.011) after multivariable adjustment. CONCLUSION: SSc patients show an abnormal lipid profile with respect to controls including CEC. Skin thickness is independent and inversely associated with CEC in SSc patients.

Differences in Capacity of High-Density Lipoprotein Cholesterol Efflux Between Patients With Systemic Lupus Erythematosus and Rheumatoid Arthritis.

OBJECTIVE: Cholesterol efflux capacity (CEC) is the ability of high-density lipoprotein (HDL) cholesterol to accept cholesterol from macrophages. Lipid profiles and CEC appear to be altered in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) due to disease activity and inflammation. CEC has been linked to cardiovascular events in the general population and to subclinical atherosclerosis in SLE and RA patients. The aim of this study was to establish whether CEC varies between patients with SLE and those with RA. METHODS: The study encompassed 460 individuals (195 SLE patients and 265 patients with RA). CEC (using an in vitro assay) and concentrations of lipoprotein serum were assessed in both populations. A multivariable regression analysis was performed to study whether CEC differs between SLE patients and RA patients. RESULTS: Comparison of lipid patterns revealed that patients with RA have lower HDL cholesterol and higher apolipoprotein B serum levels than SLE patients. CEC was downregulated in SLE patients compared to patients with RA (ß -12 [95% confidence interval -13, -10], P < 0.001). It occurred independently of traditional cardiovascular risk factors, statin use, disease-related data, and other variations in the lipid profile related to the diseases. CONCLUSION: Patients with RA have a more proatherogenic lipid pattern compared to those with SLE. However, CEC seems to be more damaged in SLE patients than in RA patients.

Higher Prevalence and Degree of Insulin Resistance in Patients With Rheumatoid Arthritis Than in Patients With Systemic Lupus Erythematosus.

OBJECTIVE: Since insulin resistance (IR) is highly prevalent in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), we aimed to determine whether differences in IR exist between the two conditions. METHODS: We conducted a cross-sectional study comprising 413 subjects without diabetes (186 with SLE and 227 with RA). Glucose, insulin, and C-peptide serum levels, as well as IR by the homeostatic model assessment (HOMA2) were studied. A multivariable regression analysis was performed to evaluate the differences in IR indexes between patients with SLE and RA, as well as to determine if IR risk factors or disease-related characteristics are differentially associated with IR in both populations. RESULTS: The insulin:C-peptide molar ratio was upregulated in patients with RA compared to patients with SLE (ß 0.009, 95% CI 0.005-0.014, P < 0.001) after multivariable analysis. HOMA2 indexes related to insulin sensitivity (HOMA2-%S) were found to be lower (ß -27, 95% CI -46 to -9, P = 0.004) and ß cell function (HOMA2-%B) showed higher IR indexes (ß 38, 95% CI 23-52, P < 0.001) in RA than in SLE patients after multivariable analysis. Patients with RA more often fulfilled the definition of IR than those with SLE (OR 2.15, 95% CI 1.25-3.69, P = 0.005). The size effect of IR factors on IR indexes was found to be equal in both diseases. CONCLUSION: IR sensitivity is lower and ß cell function is higher in RA than in SLE patients. The fact that traditional IR factors have an equal effect on IR in both SLE and RA supports the contention that these differences are related to the diseases themselves.

Proprotein convertase subtilisin/kexin type 9 in the dyslipidaemia of patients with axial spondyloarthritis is related to disease activity.

OBJECTIVE: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease that regulates cholesterol metabolism and has been linked to cardiovascular (CV) risk. The purpose of the present study was to examine whether PCSK9 levels are related to abnormalities in the lipid profile and the development of atherosclerosis that occurs in patients with axial SpA (axSpA). METHODS: We performed a cross-sectional study that encompassed 545 individuals; 299 patients with axSpA and 246 statin use-matched controls. PCSK9 and standard lipid profiles were analysed in patients and controls. Carotid intima-media thickness (cIMT) and carotid plaques were assessed in patients. A multivariable analysis, adjusted for standard CV risk factors, was performed to evaluate the influence of PCSK9 on axSpA-related dyslipidaemia and subclinical carotid atherosclerosis. RESULTS: Total cholesterol, high-density lipoprotein and low density lipoprotein cholesterol, lipoprotein (a) and apolipoprotein A1 were significantly lower in axSpA patients than controls. PCSK9 serum levels [ß coefficient -44 ng/dl (95% CI -60, -27), P = 0.000] were also downregulated in axSpA patients after fully multivariable adjustment. ASDAS-CRP was found to be independently and significantly related to PCSK9 [ß coefficient 10 ng/dl (95% CI 1, 18), P = 0.023] after analysing fully adjusted models that took age, sex and the rest of the lipid profile molecules into account. Whereas patients taking prednisone showed higher serum levels of PCSK9 [55 ng/ml (95% CI 24, 8), P = 0.001], those under anti-TNF-α therapies exhibited lower levels [ß coefficient -26 ng/ml (95% CI -43, -9], P = 0.003]. CONCLUSION: PCSK9 is downregulated in patients with axSpA. Disease activity is positive and significantly related to PSCK9. Anti-TNF-therapy yields a reduction in PCSK9 serum levels.

Proprotein convertase subtilisin/kexin type 9 is related to disease activity and damage in patients with systemic erythematosus lupus.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease that regulates cholesterol metabolism through low-density lipoprotein receptor degradation and that has been linked to cardiovascular (CV) disease. The purpose of the present study was to examine whether PCSK9 levels are disrupted compared with controls in patients with systemic lupus erythematosus (SLE). We additionally sought to establish whether PCSK9 is related to both the abnormalities in the lipid profile and to the disease activity or damage of patients with SLE. METHODS: We performed a cross-sectional study that encompassed 366 individuals: 195 SLE patients and 171 age-, sex-, and statin intake-matched controls. PCSK9, lipoproteins serum concentrations, and lipid profiles were assessed in patients and controls. A multivariable analysis, adjusted for standard CV risk factors, was performed to evaluate the role of PCSK9 in SLE-related dyslipidemia. RESULTS: Most lipid related-molecules were decreased in patients with SLE compared with controls. This downregulation included PCSK9, with PCSK9 levels being lower in patients than controls in the full multivariable analysis, including the modifications in lipid profiles that the disease itself produces {beta coefficient -73 [95% confidence interval (CI) -91 to -54] ng/ml, p ⩽ 0.001}. Both SLICC and SLEDAI scores were independently and positively related to PCSK9. Patients currently on hydroxychloroquine exhibited decreased levels of PCSK9 compared with those that were not taking hydroxychloroquine [beta coefficient -30 (95% CI -54 to -6) ng/ml, p = 0.015]. CONCLUSION: PCSK9 is downregulated in SLE compared with controls, but SLE patients with higher disease activity and damage exhibited higher PSCK9 serum levels.

The Number of Traditional Cardiovascular Risk Factors Is Independently Correlated with Disease Activity in Patients with Psoriatic Arthritis.

Background and objectives: Psoriatic arthritis (PsA) is associated with several comorbidities, including among others an increased risk of cardiovascular (CV) disease, atherosclerosis, metabolic syndrome, hypertension dyslipidemia, and diabetes. The purpose of the present study was to determine how the number of CV risk factors correlates with disease related data such as disease activity. Materials and Methods: Cross-sectional study that encompassed 305 patients who fulfilled the CASPAR criteria for PsA were assessed for lipid profile, disease activity measurements, and the presence of six traditional CV risk factors (diabetes mellitus, dyslipidemia, hypertension, obesity, chronic kidney disease, and smoking status). A multivariable regression analysis, adjusted for age, sex, and disease duration, was performed to evaluate if the number of classic CV risk factors was independently related with specific features of the disease, including disease activity. Results: Disease duration was found to be higher, after adjustment for age and sex, in patients with 1 or 2, and 3 or higher CV factors, compared to those patients without CV risk factors. Similarly, DAPSA (Disease Activity in PSoriatic Arthritis score) was found to be independently upregulated in patients with a higher number of CV risk factors. In this sense, as DAPSA score increases the odds ratio (OR) of having 1 or 2 (OR 1.12 (95% confidence interval (CI) 1.03-1.21), p = 0.010), and 3 or higher (OR 1.15 (95% CI 1.04-1.26), p = 0.004) CV factors was significantly higher compared to no CV risk factors category. This was independently found after adjustment for age, sex, and disease duration. Conclusions: PsA patients with a higher number of CV risk factors exhibit an upregulated disease activity compared to those without them. This is independent of disease duration and other demographics factors.

Proprotein convertase subtilisin/kexin type 9 in patients with systemic sclerosis.

OBJECTIVES: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease that regulates cholesterol metabolism through low-density lipoprotein receptor degradation, and which has been linked to cardiovascular risk. The purpose of the present study was to examine whether PCSK9 serum levels are disrupted in patients with systemic sclerosis (SS) compared to controls, and if PCSK9 is related to disease-related data and the subclinical atherosclerosis that occurs in these patients. METHODS: Cross-sectional study that encompassed 146 individuals; 73 patients with SS and 73 age- and sex-matched controls. PCSK9, lipoproteins serum concentrations, and standard lipid profiles were assessed in patients and controls. Carotid intima-media thickness (cIMT) and the presence of carotid plaques were evaluated in SS patients. A multivariable analysis, adjusted for traditional cardiovascular risk factors, was performed to evaluate the differences in PCSK9 between patients and controls, the association of SS-related manifestations with PCSK9 levels, and if PCSK9 was associated with subclinical carotid atherosclerosis in SS patients. RESULTS: After multivariable analysis, PCSK9 was downregulated in SS patients compared to controls (beta coefficient -78 (95%CI -106 - -50) ng/ml, p=0.000) and skin thickness was associated with higher serum levels of PCSK9 (beta coef. 22 (7-37) units, p=0.005). PCSK9 was significantly and positively associated with cIMT (beta coef. 0.65 (0.06-1.24) ng/ml, p=0.031) in SS patients after multivariable adjustment. CONCLUSIONS: PCSK9 serum concentration is downregulated in SS patients compared to controls and is directly associated with disease severity subrogated parameters. PCSK9 was independently related to cIMT in SS patients.

Impaired HDL cholesterol efflux capacity in systemic lupus erythematosus patients is related to subclinical carotid atherosclerosis.

OBJECTIVES: Lipid profiles appear to be altered in SLE patients due to disease activity and inflammation. Cholesterol efflux capacity (CEC) is the ability of high-density lipoprotein cholesterol to accept cholesterol from macrophages. CEC has been linked to cardiovascular events in the general population and is impaired in SLE patients. The aim of this study was to establish whether CEC is related to subclinical carotid atherosclerosis in SLE patients. METHODS: The present report is of a cross-sectional study that encompassed 418 individuals: 195 SLE patients and 223 controls. CEC, using an in vitro assay, and lipoprotein serum concentrations were assessed in patients and controls. Carotid intima-media thickness and carotid plaques were evaluated in SLE patients. A multivariable analysis was performed to study the relationship of CEC to SLE-related data, lipid profile and subclinical carotid atherosclerosis. RESULTS: CEC was downregulated in SLE patients [8.1 (4.2) % vs 16.9 (10.4) %, P = 0.004). This occurred independently of traditional cardiovascular risk factors, statin use or other variations in the lipid profile related to the disease. Traditional cardiovascular risk factors, both in patients and controls, and SLE-related data such as activity, severity or damage were not associated with CEC. After multivariable regression analysis including lipid profile-related molecules, CEC was inversely and independently associated with the presence of carotid plaques in SLE patients [odds ratio 0.87 (95% CI: 0.78, 0.97), P = 0.014]. CONCLUSION: CEC is impaired in SLE patients independently of other inflammation-related lipid profile modifications that occur during the disease. CEC is associated with carotid plaques in SLE patients.

Comparable effects of traditional cardiovascular risk factors on subclinical atherosclerosis in systemic lupus erythematosus and rheumatoid arthritis.

OBJECTIVES: Patients with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) have an increased premature prevalence of atherosclerosis. We aimed to determine whether there are differences in the prevalence of classic cardiovascular risk factors between SLE and RA. We also analysed the effect of traditional cardiovascular risk factors on the development of subclinical atherosclerosis in both conditions and if some disease-characteristic features are associated with these traditional cardiovascular risk factors. METHODS: This was a cross-sectional study encompassing 602 individuals, 276 SLE and 326 RA patients. Subclinical atherosclerosis (presence of carotid plaques and carotid intima-media thickness [cIMT]) was determined by carotid ultrasonography. A multivariable regression analysis was performed to evaluate whether classic cardiovascular-related risk factors differentially influence subclinical carotid atherosclerosis in SLE compared to RA patients. RESULTS: Age (interaction factor [if] p=0.000), hypertension (if p=0.034), and diabetes (if p=0.037) had a higher effect on cIMT in RA than in SLE subjects. However, these traditional cardiovascular factors did not yield different effects on the presence of carotid plaques in RA and SLE when the univariate interaction was analysed. In addition, no differences were found in the influence of hypertension, diabetes, dyslipidaemia or current smoking on cIMT or carotid plaque after adjusting for demographics, the presence of other traditional cardiovascular factors, and disease-related data. Moreover, the additive effect of several cardiovascular risk factors on the subclinical carotid atherosclerosis did not differ between the two diseases. CONCLUSIONS: The influence of traditional cardiovascular risk factors on cIMT and carotid plaque is similar in RA and SLE.

Viral Characteristics Associated with the Clinical Nonprogressor Phenotype Are Inherited by Viruses from a Cluster of HIV-1 Elite Controllers.

A small group of HIV-1-infected individuals, called long-term nonprogressors (LTNPs), and in particular a subgroup of LTNPs, elite controllers (LTNP-ECs), display permanent control of viral replication and lack of clinical progression. This control is the result of a complex interaction of host, immune, and viral factors. We identified, by phylogenetic analysis, a cluster of LTNP-ECs infected with very similar low-replication HIV-1 viruses, suggesting the contribution of common viral features to the clinical LTNP-EC phenotype. HIV-1 envelope (Env) glycoprotein mediates signaling and promotes HIV-1 fusion, entry, and infection, being a key factor of viral fitness in vitro, cytopathicity, and infection progression in vivo Therefore, we isolated full-length env genes from viruses of these patients and from chronically infected control individuals. Functional characterization of the initial events of the viral infection showed that Envs from the LTNP-ECs were ineffective in the binding to CD4 and in the key triggering of actin/tubulin-cytoskeleton modifications compared to Envs from chronic patients. The viral properties of the cluster viruses result in a defective viral fusion, entry, and infection, and these properties were inherited by every virus of the cluster. Therefore, inefficient HIV-1 Env functions and signaling defects may contribute to the low viral replication capacity and transmissibility of the cluster viruses, suggesting a direct role in the LTNP-EC phenotype of these individuals. These results highlight the important role of viral characteristics in the LTNP-EC clinical phenotype. These Env viral properties were common to all the cluster viruses and thus support the heritability of the viral characteristics.IMPORTANCE HIV-1 long-term nonprogressor elite controller patients, due to their permanent control of viral replication, have been the object of numerous studies to identify the factors responsible for this clinical phenotype. In this work, we analyzed the viral characteristics of the envelopes of viruses from a phylogenetic cluster of LTNP-EC patients. These envelopes showed ineffective binding to CD4 and the subsequent signaling activity to modify actin/tubulin cytoskeletons, which result in low fusion and deficient entry and infection capacities. These Env viral characteristics could explain the nonprogressor clinical phenotype of these patients. In addition, these inefficient env viral properties were present in all viruses of the cluster, supporting the heritability of the viral phenotype.

Membrane dynamics associated with viral infection.

Viral replication and spreading are fundamental events in the viral life cycle, accounting for the assembly and egression of nascent virions, events that are directly associated with viral pathogenesis in target hosts. These processes occur in cellular compartments that are modified by specialized viral proteins, causing a rearrangement of different cell membranes in infected cells and affecting the ER, mitochondria, Golgi apparatus, vesicles and endosomes, as well as processes such as autophagic membrane flux. In fact, the activation or inhibition of membrane trafficking and other related activities are fundamental to ensure the adequate replication and spreading of certain viruses. In this review, data will be presented that support the key role of membrane dynamics in the viral cycle, especially in terms of the assembly, egression and infection processes. By defining how viruses orchestrate these events it will be possible to understand how they successfully complete their route of infection, establishing viral pathogenesis and provoking disease.

The HDAC6/APOBEC3G complex regulates HIV-1 infectiveness by inducing Vif autophagic degradation.

BACKGROUND: Human immunodeficiency virus type 1 (HIV-1) has evolved a complex strategy to overcome the immune barriers it encounters throughout an organism thanks to its viral infectivity factor (Vif), a key protein for HIV-1 infectivity and in vivo pathogenesis. Vif interacts with and promotes "apolipoprotein B mRNA-editing enzyme-catalytic, polypeptide-like 3G" (A3G) ubiquitination and subsequent degradation by the proteasome, thus eluding A3G restriction activity against HIV-1. RESULTS: We found that cellular histone deacetylase 6 (HDAC6) directly interacts with A3G through its C-terminal BUZ domain (residues 841-1,215) to undergo a cellular co-distribution along microtubules and cytoplasm. The HDAC6/A3G complex occurs in the absence or presence of Vif, competes for Vif-mediated A3G degradation, and accounts for A3G steady-state expression level. In fact, HDAC6 directly interacts with and promotes Vif autophagic clearance, thanks to its C-terminal BUZ domain, a process requiring the deacetylase activity of HDAC6. HDAC6 degrades Vif without affecting the core binding factor ß (CBF-ß), a Vif-associated partner reported to be key for Vif- mediated A3G degradation. Thus HDAC6 antagonizes the proviral activity of Vif/CBF-ß-associated complex by targeting Vif and stabilizing A3G. Finally, in cells producing virions, we observed a clear-cut correlation between the ability of HDAC6 to degrade Vif and to restore A3G expression, suggesting that HDAC6 controls the amount of Vif incorporated into nascent virions and the ability of HIV-1 particles of being infectious. This effect seems independent on the presence of A3G inside virions and on viral tropism. CONCLUSIONS: Our study identifies for the first time a new cellular complex, HDAC6/A3G, involved in the autophagic degradation of Vif, and suggests that HDAC6 represents a new antiviral factor capable of controlling HIV-1 infectiveness by counteracting Vif and its functions.

Gelsolin activity controls efficient early HIV-1 infection.

BACKGROUND: HIV-1 entry into target lymphocytes requires the activity of actin adaptors that stabilize and reorganize cortical F-actin, like moesin and filamin-A. These alterations are necessary for the redistribution of CD4-CXCR4/CCR5 to one pole of the cell, a process that increases the probability of HIV-1 Envelope (Env)-CD4/co-receptor interactions and that generates the tension at the plasma membrane necessary to potentiate fusion pore formation, thereby favouring early HIV-1 infection. However, it remains unclear whether the dynamic processing of F-actin and the amount of cortical actin available during the initial virus-cell contact are required to such events. RESULTS: Here we show that gelsolin restructures cortical F-actin during HIV-1 Env-gp120-mediated signalling, without affecting cell-surface expression of receptors or viral co-receptor signalling. Remarkably, efficient HIV-1 Env-mediated membrane fusion and infection of permissive lymphocytes were impaired when gelsolin was either overexpressed or silenced, which led to a loss or gain of cortical actin, respectively. Indeed, HIV-1 Env-gp120-induced F-actin reorganization and viral receptor capping were impaired under these experimental conditions. Moreover, gelsolin knockdown promoted HIV-1 Env-gp120-mediated aberrant pseudopodia formation. These perturbed-actin events are responsible for the inhibition of early HIV-1 infection. CONCLUSIONS: For the first time we provide evidence that through its severing of cortical actin, and by controlling the amount of actin available for reorganization during HIV-1 Env-mediated viral fusion, entry and infection, gelsolin can constitute a barrier that restricts HIV-1 infection of CD4+ lymphocytes in a pre-fusion step. These findings provide important insights into the complex molecular and actin-associated dynamics events that underlie early viral infection. Thus, we propose that gelsolin is a new factor that can limit HIV-1 infection acting at a pre-fusion step, and accordingly, cell-signals that regulate gelsolin expression and/or its actin-severing activity may be crucial to combat HIV-1 infection.