Improvement Of Vascular Inflammation Research Articles

Psoriasis and metabolic syndrome: implications for the management and treatment of psoriasis.

Psoriasis is a chronic systemic inflammatory disorder associated with several comorbidities in addition to the characteristic skin lesions. Metabolic syndrome (MetS) is the most frequent comorbidity in psoriasis and a risk factor for cardiovascular disease, a major cause of death among patients with psoriasis. Although the exact causal relationship between these two disorders is not fully established, the underlying pathophysiology linking psoriasis and MetS seems to involve overlapping genetic predispositions and inflammatory pathways. Dysregulation of the IL‐23/Th‐17 immune signalling pathway is central to both pathologies and may be key to promoting susceptibility to metabolic and cardiovascular diseases in individuals with and without psoriasis. Thus, biological treatments for psoriasis that interrupt these signals could both reduce the psoriatic inflammatory burden and also lessen the risk of developing atherosclerosis and cardiometabolic diseases. In support of this hypothesis, improvement of skin lesions was associated with improvement in vascular inflammation in recent imaging studies, demonstrating that the beneficial effect of biological agents goes beyond the skin and could help to prevent cardiovascular disease. This review will summarize current knowledge on underlying inflammatory mechanisms shared between psoriasis and MetS and discuss the most recent clinical evidence for the potential for psoriasis treatment to reduce cardiovascular risk.

The Ribonucleotide Reductase Inhibitor, Didox, Reduces the In Vivo Vascular Inflammation and Oxidative Stress Induced By Acute Hemolysis

Introduction: Several diseases and disorders, including hereditary and acquired hemolytic anemia, blood transfusion reactions, preeclampsia and some infections, incur intravascular hemolysis to varying degrees. The destruction of red blood cells and the release of hemoglobin (Hb) and heme into the circulation results in vascular inflammation, characterized by the recruitment of leukocytes to the vascular endothelium, reduced nitric oxide bioavailability and oxidative stress, all of which may contribute to complications seen in hemolytic diseases, such as pulmonary hypertension, cutaneous leg ulcers and priapism. Didox (3,4-dihydroxybenzohydroxamic acid), a ribonucleotide reductase inhibitor, has been shown to have anti-inflammatory and anti-oxidative effects. This molecule has potential as a cancer therapy and has demonstrated beneficial effects in numerous pathologies, diminishing vaso-occlusive processes in mice with sickle cell disease, and suppressing mast cell activation and degranulation, amongst other effects. Aims: The aim of this study was to evaluate the effects of didox on the vascular inflammatory effects of in vivo acute hemolysis. Methods: C57BL/6 mice received i.v. didox (10 mg/animal) or the same volume of saline vehicle immediately before receiving the hemolytic stimulus. In some mice, didox (10 mg) was given intraperitonally (i.p.) 30 min before hemolysis. Acute hemolysis (HEM) was induced by injecting mice (i.v.) with 100 µl sterile water; for non-hemolysis controls (CON), the same quantity of saline was administered i.v.. At 15 min post-hemolysis, blood was obtained by cardiac puncture for biochemical and flow cytometry analyses; other animals were submitted to cremaster muscle exposure followed by intravital microscopy. Results: Intravascular H2O administration successfully induced hemolysis within 15 min, as demonstrated by elevated plasma cell-free Hb and heme levels (plasma Hb: 0.20±0.05 and 0.66±0.16 mg/ml, P<0.01; total plasma heme: 26.3±4.9 and 87.1±18.4 µM, for CON and HEM, respectively, N=≥6, P<0.001). Interestingly, pre-administration of mice with didox slightly, but significantly, decreased plasma Hb and Heme (plasma Hb: 0.43±0.07 and 0.54±0.07 mg/ml, P<0.05; total plasma heme: 62.7.3±9.5 and 71.5±6.7 µM for i.v. and i.p. didox, respectively, N=6, P<0.05). Concomitantly, acute hemolysis significantly augmented leukocyte (WBC) recruitment and extravasation in the cremaster microcirculation (WBC adhesion: 3.07±0.28 and 13.41±1.02 WBC µm-1, P<0.001; WBC extravasation: 0.72±0.16 and 2.93±0.45 WBC (100x50 µm-2) for CON and HEM, respectively, N=≥5, P<0.001). Didox significantly abrogated this effect of hemolysis, decreasing WBC adhesion to 6.12±0.62 and 2.10±0.30 WBC µm-1 and WBC extravasation to 1.32±0.24 and 1.14±0.21 WBC (100x50 µm-2) (for i.v. and i.p. didox, respectively, N≥5, P<0.001). Flow cytometry demonstrated that hemolysis elevated both the generation of reactive oxygen species (ROS) in the granulocytes of mice and their expression of the Mac-1 integrin subunit, CD11b (ROS: 590±58 and 1140±187 MFI, P<0.01; CD11b: 3028±387 and 4534±416 MFI, for CON and HEM, respect. N=3-6, P<0.01). Importantly, the inhibition of vascular inflammation by didox was associated with a significant decrease in both ROS generation and CD11b expression by granulocytes (ROS: 591±53 and 699±120 MFI, P<0.01; CD11b 2399±126 and 2379±207 MFI, for i.v. and i.p. didox, respectively. N=3-6, P<0.01). Conclusion: Didox, when administrated both intravascularly and intraperitoneally in mice, can inhibit the significant elevations in leukocyte integrin expression and cellular recruitment in the microcirculation that are induced by acute hemolysis. This improvement in vascular inflammation is accompanied by the prevention of oxidative stress in the leukocytes. While didox was found to slightly reduce hemolysis in response to osmotic shock, an interesting observation in itself, it is probable that the beneficial effects of this molecule on vascular inflammation are mediated largely by its effect on oxidative stress parameters. As such, this molecule may provide a novel therapeutic approach to reduce the oxidative stress and vascular inflammation caused by hemolytic events. This includes potential clinical use to treat sickle cell disease and other disorders in which hemolysis is a contributing factor to the pathophysiology. DisclosuresElford:Molecules for Health, Inc.: Equity Ownership, Patents & Royalties: Didox.

Association of Tumor Necrosis Factor Inhibitor Treatment With Reduced Indices of Subclinical Atherosclerosis in Patients With Psoriatic Disease.

To assess the effect of tumor necrosis factor inhibitors (TNFi) on subclinical cardiovascular disease in patients with psoriatic disease. We performed a 2-stage study. In stage 1, carotid total plaque area was assessed in patients with psoriasis or psoriatic arthritis (PsA) (n = 319) by ultrasound at baseline and after 2-3 years. The annual progression rate of atherosclerosis was the outcome of interest. In stage 2, PsA patients receiving TNFi (n = 21) and age- and sex-matched PsA patients not receiving any biologic agent (n = 13) underwent 18 F-fluorodeoxyglucose-positron emission tomography/computed tomography at baseline and 1 year to assess vascular inflammation, measured as target-to-background ratio (TBR). In both stages, multivariable regression analyses adjusted for cardiovascular risk factors and use of statins were performed. In stage 1, men had significantly higher atherosclerosis progression than women (P < 0.001). TNFi was associated with reduced atherosclerosis progression in men after controlling for cardiovascular risk and use of statins (adjusted β = -2.20 [95% confidence interval -3.41, -1.00], P < 0.001). There was no association between TNFi and atherosclerosis progression in women (P = 0.74). In stage 2, patients receiving TNFi had reduced TBR at 1 year (P = 0.03). Those not receiving TNFi had no significant change in TBR (P = 0.32). The improvement in aortic vascular inflammation in the TNFi group was independent of cardiovascular risk factors (adjusted β = -0.41 [95% confidence interval -0.74, -0.08], P = 0.02). Our findings indicate that TNFi treatment is associated with reduced progression of carotid plaques in men and improvement in vascular inflammation in both men and women with psoriatic disease.

Abstract 12593: Improvement in Aortic Vascular Inflammation by 18-FDG PET/CT Associates With Reduction in Aortic Wall Thickness by MRI

Introduction: The presence of aortic vascular inflammation (VI) by 18-FDG PET/CT predicts future cardiovascular (CV) events. Furthermore, aortic wall thickness by MRI has been shown to be an important marker of early subclinical atherosclerosis. Whether improvement in aortic vascular inflammation by FDG PET/CT is associated with improvement in aortic wall thickness by MRI is not known. Hypothesis: We hypothesized that an improvement in VI by FDG PET/CT will associate with an improvement in aortic wall thickness by MRI in a well characterized cohort of Psoriasis (PSO) patients. Methods: Consecutively recruited PSO patients (N=64) underwent whole-body PET/CT and MRI exams at baseline and 1-year follow-up. VI was assessed as target-to-background ratio (TBR) [Excellence Brilliant Workstation]. To measure aortic wall thickness, wall boundaries of the thoracic descending aorta were traced on each MRI slice [Qplaque, Medis]. The longitudinal change in wall thickness of the thoracic descending aorta was analyzed using unadjusted and adjusted multivariable regression (STATA 12). Results: The cohort was middle-aged (mean±SEM 50.67±1.80) and had a low cardiovascular risk by Framingham risk score [median-3, IQR- (1-7)]. Overall the cohort had an average TBR of 1.74±0.02 consistent with moderate vascular inflammation. At follow-up, the total cohort had a mean improvement in TBR of 7.47% (p&lt;0.001) with use of topical therapy (64%), biological therapy (59%) and UVB (13%). Improvement in TBR of the aorta was associated with reduction in mean wall thickness of the descending thoracic aorta beyond adjustment for traditional risk factors, statin use, &amp; systemic/biologic PSO therapy (β=0.30, p = 0.03). Conclusions: Improvement in aortic VI by FDG PET/CT was associated with reduction in aortic wall thickness by MRI at one year, suggesting a reduction in VI may improve early atherosclerosis. Our findings suggest that an improvement in vascular inflammation may mitigate structural abnormalities of the aorta. Randomized controlled studies are needed to confirm these findings.

Berberine Attenuates Vascular Remodeling and Inflammation in a Rat Model of Metabolic Syndrome.

Berberine is a natural product that shows benefits for metabolic syndrome (MS). However, the effects of berberine on the improvement of vascular inflammation and remodeling in MS remain unclear. This study aimed to investigate whether berberine could prevent vascular remodeling and inflammation in the MS condition. A rat model of MS was established, and MS rats were divided into two groups: MS group without berberine treatment, and MSB group with berberine treatment (each group n-10). Ten normal Wistar rats were used as controls (NC group). Vascular damage was examined by transmission electron microscopy and pathological staining. Compared to the NC group, the secretion of inflammatory factors was increased and the aortic wall thicker in the MS group. The MSB group exhibited decreased secretion of inflammatory factors and improved vascular remodeling, compared to the MS group. In addition, the levels of p38 mitogen-activated protein kinase (p38 MAPK), activating transcription factor 2 (ATF-2) and matrix metalloproteinase 2 (MMP-2) were significantly decreased in the MSB group compared to the MS group. In conclusion, our data show that berberine improves vascular inflammation and remodeling in the MS condition, and this is correlated with the ability of berberine to inhibit p38 MAPK activation, ATF-2 phosphorylation, and MMP-2 expression.

Telmisartan Treatment Decreases Visceral Fat Accumulation and Improves Serum Levels of Adiponectin and Vascular Inflammation Markers in Japanese Hypertensive Patients

Hypertension contributes to the occurrence and progression of cardiovascular diseases. The angiotensin II type 1 receptor blocker telmisartan is reported to activate the peroxisome proliferator-activated receptor gamma and improve insulin sensitivity. We investigated the effects of telmisartan treatment on visceral fat, serum adiponectin and vascular inflammation markers in Japanese hypertensive patients. This was an open-label, non-controlled study. Twenty-eight essential hypertensive patients (22 men and 6 women; age 60.6+/-1.9 years; body mass index [BMI] 25.5+/-0.6 kg/m(2)) participated. Fat area was assessed with computerized tomography. All the subjects were started on telmisartan 40 mg/day, which was increased to 80 mg/day to achieve the blood pressure target of less than 130/80 mmHg. We assessed the visceral and subcutaneous fat areas, serum adiponectin levels, and vascular inflammation markers at baseline and 24 weeks of telmisartan treatment. There were significant reductions in visceral fat area (from 103.1+/-7.9 to 93.3+/-8.4 cm(2), p<0.01) and pulse wave velocity (from 1,706+/-52 to 1,587+/-51 cm/s, p<0.01) at 24 weeks. In contrast, significant increases in serum high-density lipoprotein cholesterol (from 5.06+/-0.15 to 5.32+/-0.13 mmol/L, p<0.05) and adiponectin levels (from 8.27+/-0.76 to 9.13+/-0.81 microg/mL, p<0.05) were observed. Also, there were reductions in the interleukin-6 level (from 2.26+/-0.27 to 1.60+/-0.14 pg/mL, p<0.01). We also conducted these investigations in male subjects alone and similar findings were obtained for all of these parameters. In conclusion, telmisartan treatment was associated with an improvement of vascular inflammation, reductions in visceral fat and increases in serum adiponectin.