Dietary 23-hydroxy ursolic acid protects against atherosclerosis and obesity by preventing dyslipidemia-induced monocyte priming and dysfunction.

BACKGROUND AND AIMS: We demonstrated that dietary ursolic acid (UA) reduces atherosclerotic lesion size and improves kidney function in diabetic mice. Based on structure-function analyses of naturally occurring UA analogs, we synthesized 23-hydroxy ursolic acid (23-OHUA), a compound with structural features predicted to enhance its bioavailability and anti-atherogenic properties compared to UA. The goal of this study was to determine the anti-obesogenic and atheroprotective properties of 23-OHUA and its mechanism of action. METHODS: We performed chemotaxis assays to determine IC50 of phytochemicals on primed THP-1 monocytes. We fed 12-week old female LDLR-/- mice a high-fat diet (HFD) or a HFD supplemented with either 0.05% UA or 0.05% 23-OHUA, and measured monocyte priming, weight gain and atherosclerotic lesion size after 6 and 20 weeks. RESULTS: Both dietary UA and 23-OHUA prevented dyslipidemia-induced loss of MKP-1 activity, and hyper-chemotactic activity, hallmarks of blood monocytes priming and dysfunction, but they did not affect plasma lipids or blood glucose levels nor WBC and monocyte counts. After 20 weeks, mice fed 23-OHUA showed 11% less weight gain compared to HFD-fed control mice and a 40% reduction in atherosclerotic plaque size, whereas UA reduced lesion size by only 19% and did not reduce weight gain. CONCLUSIONS: Dietary 23-OHUA reduces weight gain and attenuates atherogenesis in mice by protecting monocytes against metabolic stress-induced priming and dysfunction. Based on its mechanism of action, 23-OHUA may represent a novel therapeutic approach for the prevention and treatment of obesity and atherosclerosis.

DUSP1 Is a Potential Marker of Chronic Inflammation in Arabs with Cardiovascular Diseases.

BACKGROUND: Cardiovascular disease (CVD) risks persist in patients despite the use of conventional treatments. This might be due to chronic inflammation as reflected in epidemiological studies associating circulating low-grade inflammatory markers with CVD recurrent events. Here, we explored this potential link by assessing plasma dual-specificity phosphatase 1 (DUSP1) levels and comparing them to high-sensitivity CRP (hsCRP) and oxidized low-density lipoprotein (oxLDL) levels and their associations to conventional CVD risk factors in confirmed CVD patients. METHODS: Human adults with reported CVD (n = 207) and controls (n = 70) living in Kuwait were used in this study. Anthropometric and classical biochemical parameters were determined. Plasma levels of DUSP1, oxLDL, and hsCRP were measured using human enzyme-linked immunosorbent assay kits. RESULTS: DUSP1 and hsCRP plasma levels and their least square means were higher in CVD cases, while oxLDL plasma levels were lower (p < 0.05). Multivariate logistic regression analysis showed that DUSP1 and hsCRP are independently associated with CVD in the studied population, as reflected by 2-fold and 1.5-fold increased risks with increased levels of DUSP1 and hsCRP, respectively. In our study, DUSP1 levels were found to be associated with CVD despite statin treatment and diabetes status (p < 0.05), whereas hsCRP mainly correlated with obesity markers. CONCLUSIONS: Circulating DUSP1 might be a predictor of chronic subclinical inflammation and residual risk in CVD patients, whereas our data suggest that the association between hsCRP and CVD is largely accounted for adiposity risk factors.

Association Between MKP-1, BDNF, and Gonadal Hormones with Depression on Perimenopausal Women.

BACKGROUND: Studies suggest that brain-derived neurotrophic factor (BDNF) exerts effects on the neuronal function of hippocampal neurons and increases hippocampal mitogen-activated protein kinase phosphatase-1 (MKP-1) expression, which causes depressive behaviors in rat or mouse. Here we focus on the change of serum MKP-1, BDNF, testosterone (T), and estradiol (E2) levels, in order to test the hypothesis that dysregulation of MKP-1, BDNF, T, and E2 are associated with depression in perimenopausal women. METHODS: Women with depression, after meeting criteria in the International Statistical Classification of Diseases and Related Health Problems, 10th Revision, for mental and behaviural disorders and the 17-item Hamilton Depression Rating Scale (HDRS), were included in the study. Psychosocial data and blood samples were obtained from the subjects in the study, including 38 perimenopausal and 32 young women with depression, 26 healthy control perimenopausal women, and 34 young women. RESULTS: Serum MKP-1 levels were higher and T was lower in the women with depression compared to controls (p<0.05), and depressed perimenopausal women exhibited the highest serum MKP-1 levels and lowest T levels. Logistic regression analyses showed that MKP-1 levels were positively correlated with HDRS scores in the women, and T levels were inversely correlated with HDRS scores in the perimenopausal women (p<0.05). CONCLUSIONS: This study suggests that high serum MKP-1 levels are associated with depression in women, and this association did not appear to be confounded by age. Further, the results provide evidence of association between depressive symptom severity and increasing serum MKP-1 levels in women, and decreasing T levels in perimenopausal women.

Obstructive sleep apnea and intermittent hypoxia increase expression of dual specificity phosphatase 1.

OBJECTIVE: Dual specificity phosphatase 1 (DUSP1) inhibits mitogen activated protein kinase activity, and is activated by several stimuli such as sustained hypoxia, oxidative stress, and hormones. However, the effect of intermittent hypoxia is not known. The aim of this study was to evaluate the role of intermittent hypoxia on DUSP1 expression, and to validate its role in a human model of intermittent hypoxia, as seen in obstructive sleep apnea (OSA). OSA is characterized by recurrent episodes of hypoxemia/reoxygenation and is a known risk factor for cardiovascular morbidity. METHODS: In-vitro studies using human coronary artery endothelial cells (HCAEC) and ex-vivo studies using white blood cells isolated from healthy and OSA subjects. RESULTS: Intermittent hypoxia induced DUSP1 expression in human coronary artery endothelial cells (HCAEC), and in granulocytes isolated from healthy human subjects. Functionally, DUSP1 increased the expression and activity of manganese superoxide dismutase (MnSOD) in HCAEC. Further, significant increases in DUSP1 mRNA from total blood, and in DUSP1 protein in mononuclear cells and granulocytes isolated from OSA subjects, were observed in the early morning hours after one night of intermittent hypoxemia due to untreated OSA. This early-morning OSA-induced augmentation of DUSP1 gene expression was attenuated by continuous positive airway pressure (CPAP) treatment of OSA. CONCLUSION: Intermittent hypoxia increases MnSOD activity via increased DUSP1 expression in HCAEC. Similarly, overnight intermittent hypoxemia in patients with OSA induces expression of DUSP1, which may mediate increases of MnSOD expression and activity. This may contribute significantly to neutralizing the effects of reactive oxygen species, a consequence of the intermittent hypoxemia/reperfusion elicited by OSA.

Blood levels of dual-specificity phosphatase-1 independently predict risk for post-operative morbidities causing prolonged hospitalization after coronary artery bypass grafting.

New technologies to generate high-dimensional data provide unprecedented opportunities for unbiased identification of biomarkers that can be used to optimize pre-operative planning, with the goal of avoiding costly post-operative complications and prolonged hospitalization. To identify such markers, we studied the global gene expression profiles of three organs central to the metabolic and inflammatory homeostasis isolated from coronary artery disease (CAD) patients during coronary artery bypass grafting (CABG) surgery. A total of 198 whole-genome expression profiles of liver, skeletal muscle and visceral fat from 66 CAD patients of the Stockholm Atherosclerosis Gene Expression (STAGE) cohort were analyzed. Of ~50,000 mRNAs measured in each patient, the mRNA levels of the anti-inflammatory gene, dual-specificity phosphatase-1 (DUSP1) correlated independently with post-operative stay, discriminating patients with normal (≤8 days) from those with prolonged (>8 days) hospitalization (p<0.004). To validate DUSP1 as a marker of risk for post-operative complications, we prospectively analyzed 181 patients undergoing CABG at Tartu University Hospital for DUSP1 protein levels in pre-operative blood samples. The pre-operative plasma levels of DUSP1 clearly discriminated patients with normal from those with prolonged hospitalization (p=2x10-13; odds ratio = 5.1, p<0.0001; receiver operating characteristic area under the curve = 0.80). Taken together, these results indicate that blood levels of the anti-inflammatory protein DUSP1 can be used as a biomarker for post-operative complications leading to prolonged hospitalization after CABG and therefore merit further testing in longitudinal studies of patients eligible for CABG.

Exercise training upregulates macrophage MKP-1 and affects immune responses in mice.

PURPOSE: Currently, it is unclear how chronic exercise affects immunity. Mitogen-activated protein kinase (MAPK) mediates the production of proinflammatory cytokines, whereas MAPK phosphatase-1 (MKP-1) plays an essential role in intracellular homeostasis by negatively regulating macrophage MAPK activation. We hypothesized that chronic exercise might upregulate macrophage MKP-1 and thus prevent excessive inflammatory responses. METHODS: To verify this hypothesis, we compared the basal immune status and lipopolysaccharide (LPS)-evoked immune responses between sedentary and 8-wk treadmill exercise-trained male C57BL/6 mice. RESULTS: Although the basal levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were undetectable in the serum of both groups, the exercised mice showed the following immune adaptations in vivo: (i) higher basal MKP-1 mRNA level in peritoneal macrophages, (ii) lower basal p38 MAPK activity and enhanced MKP-1 immunostaining in macrophages, and (iii) lower serum levels of IL-6 and TNF-α and less leukocyte infiltration into peritoneal cavity after systemic administration of LPS when compared with sedentary controls. In addition, when peritoneal macrophages isolated from exercised mice were exposed to LPS in vitro, they showed (i) accelerated MKP-1 protein expression, (ii) reduced p38 MAPK activity, and (iii) reduced cytokine secretion of IL-6, TNF-α, and monocyte chemotactic protein-1. Finally, 2 months of deconditioning completely reversed the exercise-enhanced basal MKP-1 immunostaining in macrophages and the exercise-suppressed cytokine secretion under LPS-evoked conditions. CONCLUSIONS: Exercise training upregulated basal macrophage MKP-1 expression, accelerated LPS-evoked MKP-1 up-regulation, and affected LPS-evoked immune responses in mice.