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Plasma soluble P-selectin correlates with triglycerides and nitrite in overweight/obese patients with schizophrenia

Plasma soluble P-selectin correlates with triglycerides and nitrite in overweight/obese patients... Pteridines 2020; 31: 61–67 Research Article Open Access Katelynn A. Bourassa, Teodor T. Postolache, Aline Dagdag, Dietmar Fuchs, Olaoluwa O. Okusaga* Plasma soluble P-selectin correlates with triglycerides and nitrite in overweight/obese patients with schizophrenia https://doi.org/10.1515/pteridines-2020-0012 (primary analysis), as well as in the normal weight patients received January 8, 2020; accepted April 29, 2020. and the total sample (exploratory analyses). Abstract: Background: Soluble P-selectin (sP-selectin) Results: After controlling for potential confounders, is associated with risk factors for cardiovascular disease sP-selectin positively correlated with triglycerides (r = 0.38, (CVD) but this association has not been evaluated p = 0.01) and NO - (r = 0.40, p < 0.01) in the overweight/ in patients with schizophrenia. This study primarily obese group only. evaluated the association of sP-selectin with plasma lipids Conclusions: Future longitudinal studies should and nitrite (NO -) respectively in overweight/obese adults evaluate the utility of sP-selectin as a biomarker of CVD in with schizophrenia. overweight/obese adults with schizophrenia (for example, Methods: One-hundred and six patients with by relating sP-selectin to incidence of cardiovascular schizophrenia (mean age 32.9 years; 71.60% male) events). were recruited from a psychiatric hospital. Participants completed a structured interview and provided a fasting Keywords: schizophrenia; overweight/obesity; blood sample. Body mass index (BMI) was used to divide the P-selectin; nitrite; atherosclerosis. sample into normal weight and overweight/obese groups. Pearson’s and partial correlation coefficients (controlling for age, sex, race, education, and inflammation) were Introduction calculated to examine the association of sP-selectin with plasma lipids, and NO - in the overweight/obese patients Patients with schizophrenia have increased rates of cardiovascular disease (CVD)-related morbidity and mortality, resulting in approximately 11-20 years decreased lifespan and up to 2.5 greater odds of dying in *Corresponding author: Olaoluwa O. Okusaga, Menninger comparison to adults without a psychiatric illness [1, 2]. Department of Psychiatry and Behavioral Sciences, Baylor College of Overweight/obesity is an important factor contributing to Medicine, Houston, TX, USA, E-mail: olaoluwa.okusaga@bcm.edu CVD in patients with schizophrenia [3]. Also, overweight/ Katelynn A. Bourassa, Olaoluwa O. Okusaga, Michael E. DeBakey VA obesity in schizophrenia is considered to be in great part Medical Center, Houston, TX, USA a consequence of certain antipsychotic medications [4] Teodor T. Postolache, Aline Dagdag, Mood and Anxiety Program, Department of Psychiatry, University of Maryland School of Medicine, and is linked to a high rate of metabolic syndrome in this Baltimore, MD, USA population [5]. Teodor T. Postolache, Veterans Health Administration, Rocky Mountain Atherosclerosis, one of the main causes of CVD, is Mental Illness Research Education and Clinical Center (MIRECC), Denver characterized by an initial stage of endothelial damage Veterans Affairs Medical Center (VAMC), Aurora, CO, USA and activation [6]. After damage and activation, the Teodor T. Postolache, Military and Veteran Microbiome Consortium for endothelium expresses adhesion molecules, including Research and Education (MVM-CoRE), Aurora, CO, USA Teodor T. Postolache, VISN 5 Capitol Health Care Network Mental P-selectin, which mediate leukocyte adhesion, rolling and Illness Research Education and Clinical Center (MIRECC), Baltimore, migration into the subendothelial region [7]. P-selectin is MD, USA an important factor for atherogenesis as highlighted by Dietmar Fuchs, Division of Biological Chemistry, Biocenter Innsbruck the fact that P-selectin knockout mice exhibit negligible Medical University, Innsbruck, Austria atherosclerosis [8] while mice genetically modified to Olaoluwa O. Okusaga, Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, USA overproduce soluble P-selectin (sP-selectin) exhibit Open Access. © 2020 Katelynn A. Bourassa et al., published by De Gruyter. This work is licensed under the Creative Commons Attribution alone 4.0 License. 62  Katelynn A. Bourassa et al. accelerated rates of atherosclerosis [9]. sP-selectin is Methods derived from proteolytic cleavage of membrane-bound P-selectin or from alternative mRNA splicing [10]. Plasma Study sample sP-selectin has been found to be associated with waist circumference and other CVD risk factors (triglycerides, One-hundred and six participants were enrolled in this total cholesterol, smoking) in non-psychiatric samples cross-sectional study. All participants had a diagnosis [11]. Interestingly, elevated plasma sP-selectin has also of schizophrenia and were receiving antipsychotic been found in patients with schizophrenia [12]. medication. To be included in the study, individuals were In addition to sP-selectin expression, the initial required to: (1) be between the ages of 18 and 60, (2) have stage of atherosclerosis is also characterized by reduced a documented diagnosis of schizophrenia consistent with bioavailability of nitric oxide (NO) [13]. NO is synthesized DSM-5 criteria, and (3) have a negative urine pregnancy test in the body through the L-arginine-NO pathway which if female. Exclusion criteria included: (1) active suicidal is mainly regulated by three isoforms of the enzyme and/or homicidal ideation, (2) a history of a primary nitric oxide synthase (NOS) namely endothelial NOS cognitive disorder, (3) a current primary inflammatory (eNOS), neuronal NOS (nNOS) and inducible NOS (iNOS); condition and/or infectious disease, (4) receipt of however, eNOS and nNOS are the primary regulators under corticosteroids or non-steroidal anti-inflammatory physiological conditions [14]. The reduced bioavailability medication, (5) receipt of warfarin or other anticoagulant of NO during atherogenesis is related to its inactivation medication, and (6) current use of psychostimulant drugs, secondary to oxidative stress [15], a phenomenon that has evidenced by a positive urine drug screen. Participants also been associated with obesity in schizophrenia [16]. were recruited from the inpatient unit of a university- NO has a very short half-life therefore most investigators affiliated psychiatric hospital after approval by the estimate NO level by measuring levels of nitrate (NO -) Institutional Review Board. or nitrite (NO -), both of which are metabolites of NO Information on sex, age, race, and level of education [17]. Of note, polymorphism of the NOS3 gene (codes were obtained from each participant. The Mini for endothelial NOS, eNOS), specifically the T-786C International Neuropsychiatric Interview (a structured SNP, is associated with risk of metabolic syndrome in diagnostic interview) [20] was used to confirm the schizophrenia [18]. diagnosis of schizophrenia. Weight classification was We previously found that in overweight/obese approximated by calculating BMI. Specifically, BMI was patients with schizophrenia (but not in normal weight defined as weight (in kilograms) divided by the square patients), peripheral inflammation (assessed by of height (in meters). Participant’s height was measured plasma high sensitivity C-reactive protein [hs-CRP]) with a stadiometer and weight with an adult beam balance and triglycerides (TG) were elevated, while high-density scale. We categorized participants with BMI ≥ 25 kg/m as lipoprotein-cholesterol (HDL-C) level was low [19]. overweight/obese and those with BMI ranging from 18.5 Since dyslipidemia and NO are both involved in the 2 2 kg/m to 25 kg/m as normal weight. pathophysiology of atherosclerosis, we now aimed to Ethical approval: The research related to human use evaluate the association of sP-selectin with plasma lipids has complied with all the relevant national regulations, and NO - in the same overweight/obese patients with institutional policies and in accordance with the tenets schizophrenia. We hypothesized that in overweight/obese of the Helsinki Declaration, and has been approved by patients with schizophrenia, sP-selectin would positively the authors’ institutional review board or equivalent correlate with plasma total cholesterol (TC), TG, and low- committee. density lipoprotein-cholesterol (LDL-C), but negatively Informed consent: Informed consent has been correlate with HDL-C and NO -. On an exploratory basis we obtained from all individuals included in this study. also evaluated the association of sP-selectin with plasma lipids and NO - in the total sample (i.e. normal weight and overweight/obese patients combined) and in normal Measurement of plasma sP-selectin, lipids, weight patients alone. NO -, and hs-CRP. Fasting venous blood samples were collected (between 6am and 7am) in EDTA-containing tubes, and plasma was isolated and stored at -80 degrees Celsius until Plasma soluble P-selectin correlates with triglycerides and nitrite in overweight/obese patients with schizophrenia  63 analyzed. sP-selectin was measured using ELISA 0.01 for exploratory analyses. All analyses were performed (Enzyme-linked immunosorbent assay) kits according in IBM SPSS, Version 24 (IBM Corp., Armonk, NY, USA). to the manufacturer’s (RayBiotech, Inc. Georgia, USA) instructions. Samples were diluted 1:50 after which optical density values for the samples were compared to Results standard curves ranging from 0-30ng/ml (Assay sensitivity was 20 pg/ml). Plasma TC, TG, LDL-C, and HDL-C were measured by Quest Diagnostics (Secaucus, NJ) using Sample characteristics spectrophotometry. hs-CRP was measured using an ELISA kit (MyBioSource, MBS703598); in preparation for The overall sample was approximately 33 years of age, on analysis, samples were diluted 1:1000 and the procedures average (M = 32.9, SD = 12.3), predominantly male (n = 76; were consistent with the manufacturer’s instructions. 71.6%), and a slight majority were African American (n = Plasma nitrite was measured following the protocol 55; 51.9%). Most participants had a high school diploma outlined by Giustarini and colleagues (2004) [21] using or equivalent (n = 38; 35.9%) at the time of the study. A a modified Griess-Ilosvay diazotization reaction assay slight majority of the sample had a BMI in the overweight/ (Merk KGaA, Darmstadt, Germany). The protocol included obese range (n = 54, 53.5%). Differences in plasma lipids the reaction of sulfanilamide with NO - present in samples between overweight/obese and normal weight patients acidified with phosphoric acid, forming a diazonium are reported elsewhere [19]. See Table 1 for a depiction of salt. N-(1-naphthyl) ethylenediamine dihydrochloride sample characteristics. is then coupled with the diazonium salt forming an azo dye which was subsequently analyzed at 562 nm in a spectrophotometer (KC4 reader, Bio-Tek Instruments, Inc., Association of sP-selectin with lipids and Winooski, VT, USA). The measurement of plasma NO - NO - in overweight/obese patients was carried out at the Division of Biological Chemistry, Biocenter, Medical University of Innsbruck, Austria. Results from unadjusted analyses indicated that sP-selectin was positively correlated with TG (r = 0.40, p < 0.01) and NO - (r = 0.38, p < 0.01), but had no Statistical Analyses significant correlation with TC, LDL-C, or HDL-C. The positive correlations between sP-selectin and TG and NO - Variables were first examined for normality. sP-selectin, respectively, remained significant after controlling for hs-CRP, and NO - were skewed to the right and a log potential confounders (r = 0.38, p = 0.01 and r = 0.40, p < transformation was performed on each variable. Means 0.01 respectively). See Table 2. ± standard deviation or percentages (as appropriate) are presented for descriptive variables. For sP-selectin, hs-CRP, and NO -, we have presented geometric means Association of sP-selectin with lipids and obtained by exponentiating the mean log-transformed NO - in the normal weight participants and in values. To examine the primary hypothesis that plasma the total sample sP-selectin is associated with plasma lipids and NO - in overweight/obese patients, Pearson’s correlations sP-selectin was not associated with plasma lipids or NO - were calculated with partial correlations to control for in either normal weight patients or in the total sample. potential confounders (i.e., sex, age, race, education and inflammation [i.e. hs-CRP]). On an exploratory basis, the correlations (Pearson’s and partial) of sP-selectin with Comparison of sP-selectin and NO - in plasma lipids and NO - were examined in the normal weight normal weight and overweight/obese patients and the entire sample (i.e., overweight/obese participants and normal weight combined). Exploratory analyses also included t-test to compare sP-selectin and NO - between sP-selectin and NO - did not differ between the normal 2 2 normal weight and overweight/obese patients. All tests weight and overweight/obese patients (43.35 ± 0.18 ng/ml were two-tailed. To control for type I error, Bonferroni vs. 38.02 ± 0.18 ng/ml, p=0.13 and; 21.44 ± 0.27 µmol/L vs. correction was applied in the primary analyses (i.e. in 24.14 ± 0.32 µmol/L, p=0.39 respectively) in this sample. overweight/obese patients only), while alpha was set at 64  Katelynn A. Bourassa et al. Table 1: Sociodemographic and metabolic characteristics of the Table 2: Correlations among sP-selectin, plasma lipids, and plasma sample (N = 106). nitrite in participants with BMI in the overweight/obese range (n = 54) before and after adjustment for sex, age, race, education, and hs-CRP. Variable Value Sex (Male; n [%]) 76 (71.60%) Pearson’s r p value Pearson’s r p value Mean Age ±SD 32.90 ±12.28 sP-selectin sP-selectin (unadjusted) (adjusted) Race n (%) TC 0.13 0.39 0.12 0.44 Caucasian 33 (31.10%) African American 55 (51.90%) TG 0.40 < 0.01 0.38 0.01 Hispanic 16 (15.10%) LDL-C 0.08 0.60 0.07 0.67 Asian 2 (1.90%) Education n (%) HDL-C -0.31 0.03 -0.31 0.04 No Degree 34 (32.10%) Plasma 0.38 < 0.01 0.40 < 0.01 High School/Equivalent 38 (35.90%) Nitrite Some College 25 (23.60%) HDL-C = High Density Lipoprotein Cholesterol; LDL-C = Low Density >2 Years College 9 (8.40%) Lipoprotein Cholesterol; r = correlation coefficient; TC = Total Mean BMI±SD 26.99±7.03 Cholesterol; TG = Triglycerides; n = 50 provided data for TC and HDL-C; n = 49 provided data for TG and LDL-C, n = 49 provided data BMI Category n (%) for plasma nitrite. Normal 47 (46.50%) Overweight/Obese 54 (53.50%) example, Belinski et al [22] found a positive correlation Geometric Mean sP-selectin (ng/ml) ±SD 40.08±0.18* between sP-selectin and both TG and LDL-C but a negative Geometric Mean hs-CRP (mg/L) ±SD 1.05±0.62* correlation with HDL-C in the Multi-Ethnic Study of Mean Total Cholesterol (mg/dL) ±SD 157.53±32.05 Atherosclerosis. Although we could not find any previous study Mean TG (mg/dL) ± SD 106.59 ± 56.89 involving patients with schizophrenia, research involving Mean LDL-C (mg/dL) ±SD 91.46±29.89 animals [23, 24] and non-psychiatric human participants Mean HDL-C (mg/dL) ±SD 44.75±14.40 [25–27] have related sP-selectin with NO - but they Geometric Mean Plasma Nitrite (µmol/L) ±SD 22.21±0.29* evaluated sP-selectin expression using other techniques (e.g. radiolabeled monoclonal antibody technique, Note. * = Geometric mean of log transformed variable; BMI = Body Western blot and flow cytometry) [24, 26, 27] rather than Mass Index; HDL-C = High Density Lipoprotein Cholesterol; hs-CRP = plasma levels as in our study. In the previous studies, High Sensitivity C-Reactive Protein; LDL-C = Low Density Lipoprotein there was a consistent finding of a negative correlation Cholesterol; sP-selectin = Soluble P-Selectin; TG = Triglycerides; 5 participants are missing BMI data between sP-selectin and NO - (as well as nitrate [NO -]). For 2 3 example, exogenously administered NO - (e.g. dietary NO - 2 2 ) attenuated P-selectin [28–30] while inhibition of NO (and Discussion therefore NO - and NO -) biosynthesis increased P-selectin 3 2 expression [26, 27]. Contrary to previous studies and We found, for the first time (to our knowledge), a our hypothesis, we found a positive correlation between positive correlation between sP-selectin and both TG sP-selectin and NO - in the subsample of overweight/ and NO - respectively in overweight/obese patients obese patients with schizophrenia after controlling for with schizophrenia but not in normal weight patients; potential confounding factors. A plausible explanation however, we did not observe any association between (though speculative) for our finding is that NO synthesis sP-selectin and TC, LDL-C, or HDL-C. Our finding of increases in parallel with sP-selectin in overweight/obese a positive relationship between sP-selectin and TG in patients as an attempt to counteract the procoagulant overweight/obese adults with schizophrenia is consistent and atherogenic effects of sP-selectin and the atherogenic with the limited literature in non-psychiatric samples. For effect of TG. It is also possible that the expression of iNOS Plasma soluble P-selectin correlates with triglycerides and nitrite in overweight/obese patients with schizophrenia  65 is increased in the overweight/obese patients since iNOS factors confounded, mediated, or moderated the observed expression is increased in obesity-induced inflammatory associations among sP-selectin, TG, and NO as suggested 2- states [31] and as described earlier, levels of inflammation by prior research reporting sP-selectin elevation in the were higher in the overweight/obese patients [19]. It is, aforementioned conditions [39, 40]. however, important to note that there was no difference in NO - levels between overweight/obese patients and normal-weight patients in this sample. Future directions Regarding the association of sP-selectin with TG in the overweight/obese patients, it is plausible to speculate The utility of sP-selectin as a potential biomarker of that it could be an indication of ensuing pathology in cardiovascular health in overweight/obese patients with the vasculature related to the combination of elevated schizophrenia should be evaluated in future prospective inflammation and hypertriglyceridemia in the overweight/ cohort studies by serial measurements of sP-selectin, obese patients [19]. This inference is consistent with the lipids, NO -, and relating them to the incidence of report of a systemic inflammatory environment inducing cardiovascular events (e.g. myocardial infarction and a phenotypic switch to a proatherogenic endothelium stroke). Other studies should also evaluate the efficacy of which leads to enhanced expression of P-selectin [32, dietary nitrite and nitrate supplementation in overweight/ 33]. The potential importance of our observed association obese patients with schizophrenia since dietary nitrite is also highlighted by the fact that recent data suggest and nitrate have been shown to increase bioavailability of that when standardized for their respective effects on NO and decrease triglyceride levels in a non-psychiatric apolipoprotein B (ApoB), TG might confer similar risk of sample [41]. Furthermore, in experimental models, CVD as LDL-C, an established CVD risk factor [34, 35]. dietary nitrite and nitrate supplementation attenuate However, we did not observe higher levels of sP-selectin the metabolic abnormalities (obesity, hyperlipidemia, in the overweight/obese patients relative to normal weight glucose intolerance, inflammation and oxidative stress) patients, a finding that is inconsistent with the preceding induced by high-fat diet in mice [42]. The effect of weight arguments and requires further exploration. loss interventions on sP-selectin and its association with Several limitations should be considered when lipids and NO -, might be also evaluated in future studies interpreting the findings of the current study. First, the since in non-psychiatric samples obese individuals who average BMI in our study population was at the lower lost 10% (or more) of their body weight in six months end of the overweight category (i.e., 26.99±7.03 kg/m ), exhibited reductions in endothelial dysfunction and and it is possible that the relationship among sP-selectin platelet activation as evidenced by platelet aggregation and plasma TG and NO - may be stronger in a more obese studies and reduced sP-selectin levels [43]. population. Additionally, average plasma lipid levels were In addition, longitudinal studies of medication naïve within the normal range for the total sample, which may patients are necessary to take into account the metabolic have resulted in an attenuated relationship with sP-selectin. effects of neuroleptics [44] as well as their potential effect Second, given the cross-sectional study design, causal on vascular dysfunction [45]. Finally, collecting larger relationships among sP-selectin, NO -, TG, overweight/ samples with greater variability in BMI status would allow obesity, cannot be established and the findings of this for a more in-depth examination of the relationships study may not generalize to other populations. Third, data among sP-selectin, plasma lipids, and NO in adults with on psychotropic medication type and dosage, important schizophrenia who have BMIs in the normal, overweight, potential confounders, were not available for this study. and obese ranges. As the affinity for weight gain differs among neuroleptics [36], we were unable to evaluate whether neuroleptics may differentially impact the relationship among Acknowledgements: Dr. Postolache’ s contribution to sP-selectin, NO -, and TG in adults with schizophrenia. this study was supported by a NORC exploratory grant (PI, Fourth, dietary sources contribute considerably to Postolache, co PI Snitker), offspring of the parent grant plasma NO - and NO - [37, 38] but since we did not collect P30 DK072488, from the NIDDK/NIH. 3 2 information on dietary intake, the possibility that our results are related to diet, cannot be ruled out. Finally, we Conflict of interest: Prof. Fuchs is Editor-in-Chief of did not collect data regarding additional CVD risk factors Pteridines. (e.g., smoking status, metabolic syndrome, diabetes). We were unable to determine whether the presence of these 66  Katelynn A. Bourassa et al. syndrome in the Old Order Amish. 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Plasma soluble P-selectin correlates with triglycerides and nitrite in overweight/obese patients with schizophrenia

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de Gruyter
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© 2020 Katelynn A. Bourassa et al., published by De Gruyter
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2195-4720
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DOI
10.1515/pteridines-2020-0012
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Abstract

Pteridines 2020; 31: 61–67 Research Article Open Access Katelynn A. Bourassa, Teodor T. Postolache, Aline Dagdag, Dietmar Fuchs, Olaoluwa O. Okusaga* Plasma soluble P-selectin correlates with triglycerides and nitrite in overweight/obese patients with schizophrenia https://doi.org/10.1515/pteridines-2020-0012 (primary analysis), as well as in the normal weight patients received January 8, 2020; accepted April 29, 2020. and the total sample (exploratory analyses). Abstract: Background: Soluble P-selectin (sP-selectin) Results: After controlling for potential confounders, is associated with risk factors for cardiovascular disease sP-selectin positively correlated with triglycerides (r = 0.38, (CVD) but this association has not been evaluated p = 0.01) and NO - (r = 0.40, p < 0.01) in the overweight/ in patients with schizophrenia. This study primarily obese group only. evaluated the association of sP-selectin with plasma lipids Conclusions: Future longitudinal studies should and nitrite (NO -) respectively in overweight/obese adults evaluate the utility of sP-selectin as a biomarker of CVD in with schizophrenia. overweight/obese adults with schizophrenia (for example, Methods: One-hundred and six patients with by relating sP-selectin to incidence of cardiovascular schizophrenia (mean age 32.9 years; 71.60% male) events). were recruited from a psychiatric hospital. Participants completed a structured interview and provided a fasting Keywords: schizophrenia; overweight/obesity; blood sample. Body mass index (BMI) was used to divide the P-selectin; nitrite; atherosclerosis. sample into normal weight and overweight/obese groups. Pearson’s and partial correlation coefficients (controlling for age, sex, race, education, and inflammation) were Introduction calculated to examine the association of sP-selectin with plasma lipids, and NO - in the overweight/obese patients Patients with schizophrenia have increased rates of cardiovascular disease (CVD)-related morbidity and mortality, resulting in approximately 11-20 years decreased lifespan and up to 2.5 greater odds of dying in *Corresponding author: Olaoluwa O. Okusaga, Menninger comparison to adults without a psychiatric illness [1, 2]. Department of Psychiatry and Behavioral Sciences, Baylor College of Overweight/obesity is an important factor contributing to Medicine, Houston, TX, USA, E-mail: olaoluwa.okusaga@bcm.edu CVD in patients with schizophrenia [3]. Also, overweight/ Katelynn A. Bourassa, Olaoluwa O. Okusaga, Michael E. DeBakey VA obesity in schizophrenia is considered to be in great part Medical Center, Houston, TX, USA a consequence of certain antipsychotic medications [4] Teodor T. Postolache, Aline Dagdag, Mood and Anxiety Program, Department of Psychiatry, University of Maryland School of Medicine, and is linked to a high rate of metabolic syndrome in this Baltimore, MD, USA population [5]. Teodor T. Postolache, Veterans Health Administration, Rocky Mountain Atherosclerosis, one of the main causes of CVD, is Mental Illness Research Education and Clinical Center (MIRECC), Denver characterized by an initial stage of endothelial damage Veterans Affairs Medical Center (VAMC), Aurora, CO, USA and activation [6]. After damage and activation, the Teodor T. Postolache, Military and Veteran Microbiome Consortium for endothelium expresses adhesion molecules, including Research and Education (MVM-CoRE), Aurora, CO, USA Teodor T. Postolache, VISN 5 Capitol Health Care Network Mental P-selectin, which mediate leukocyte adhesion, rolling and Illness Research Education and Clinical Center (MIRECC), Baltimore, migration into the subendothelial region [7]. P-selectin is MD, USA an important factor for atherogenesis as highlighted by Dietmar Fuchs, Division of Biological Chemistry, Biocenter Innsbruck the fact that P-selectin knockout mice exhibit negligible Medical University, Innsbruck, Austria atherosclerosis [8] while mice genetically modified to Olaoluwa O. Okusaga, Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, USA overproduce soluble P-selectin (sP-selectin) exhibit Open Access. © 2020 Katelynn A. Bourassa et al., published by De Gruyter. This work is licensed under the Creative Commons Attribution alone 4.0 License. 62  Katelynn A. Bourassa et al. accelerated rates of atherosclerosis [9]. sP-selectin is Methods derived from proteolytic cleavage of membrane-bound P-selectin or from alternative mRNA splicing [10]. Plasma Study sample sP-selectin has been found to be associated with waist circumference and other CVD risk factors (triglycerides, One-hundred and six participants were enrolled in this total cholesterol, smoking) in non-psychiatric samples cross-sectional study. All participants had a diagnosis [11]. Interestingly, elevated plasma sP-selectin has also of schizophrenia and were receiving antipsychotic been found in patients with schizophrenia [12]. medication. To be included in the study, individuals were In addition to sP-selectin expression, the initial required to: (1) be between the ages of 18 and 60, (2) have stage of atherosclerosis is also characterized by reduced a documented diagnosis of schizophrenia consistent with bioavailability of nitric oxide (NO) [13]. NO is synthesized DSM-5 criteria, and (3) have a negative urine pregnancy test in the body through the L-arginine-NO pathway which if female. Exclusion criteria included: (1) active suicidal is mainly regulated by three isoforms of the enzyme and/or homicidal ideation, (2) a history of a primary nitric oxide synthase (NOS) namely endothelial NOS cognitive disorder, (3) a current primary inflammatory (eNOS), neuronal NOS (nNOS) and inducible NOS (iNOS); condition and/or infectious disease, (4) receipt of however, eNOS and nNOS are the primary regulators under corticosteroids or non-steroidal anti-inflammatory physiological conditions [14]. The reduced bioavailability medication, (5) receipt of warfarin or other anticoagulant of NO during atherogenesis is related to its inactivation medication, and (6) current use of psychostimulant drugs, secondary to oxidative stress [15], a phenomenon that has evidenced by a positive urine drug screen. Participants also been associated with obesity in schizophrenia [16]. were recruited from the inpatient unit of a university- NO has a very short half-life therefore most investigators affiliated psychiatric hospital after approval by the estimate NO level by measuring levels of nitrate (NO -) Institutional Review Board. or nitrite (NO -), both of which are metabolites of NO Information on sex, age, race, and level of education [17]. Of note, polymorphism of the NOS3 gene (codes were obtained from each participant. The Mini for endothelial NOS, eNOS), specifically the T-786C International Neuropsychiatric Interview (a structured SNP, is associated with risk of metabolic syndrome in diagnostic interview) [20] was used to confirm the schizophrenia [18]. diagnosis of schizophrenia. Weight classification was We previously found that in overweight/obese approximated by calculating BMI. Specifically, BMI was patients with schizophrenia (but not in normal weight defined as weight (in kilograms) divided by the square patients), peripheral inflammation (assessed by of height (in meters). Participant’s height was measured plasma high sensitivity C-reactive protein [hs-CRP]) with a stadiometer and weight with an adult beam balance and triglycerides (TG) were elevated, while high-density scale. We categorized participants with BMI ≥ 25 kg/m as lipoprotein-cholesterol (HDL-C) level was low [19]. overweight/obese and those with BMI ranging from 18.5 Since dyslipidemia and NO are both involved in the 2 2 kg/m to 25 kg/m as normal weight. pathophysiology of atherosclerosis, we now aimed to Ethical approval: The research related to human use evaluate the association of sP-selectin with plasma lipids has complied with all the relevant national regulations, and NO - in the same overweight/obese patients with institutional policies and in accordance with the tenets schizophrenia. We hypothesized that in overweight/obese of the Helsinki Declaration, and has been approved by patients with schizophrenia, sP-selectin would positively the authors’ institutional review board or equivalent correlate with plasma total cholesterol (TC), TG, and low- committee. density lipoprotein-cholesterol (LDL-C), but negatively Informed consent: Informed consent has been correlate with HDL-C and NO -. On an exploratory basis we obtained from all individuals included in this study. also evaluated the association of sP-selectin with plasma lipids and NO - in the total sample (i.e. normal weight and overweight/obese patients combined) and in normal Measurement of plasma sP-selectin, lipids, weight patients alone. NO -, and hs-CRP. Fasting venous blood samples were collected (between 6am and 7am) in EDTA-containing tubes, and plasma was isolated and stored at -80 degrees Celsius until Plasma soluble P-selectin correlates with triglycerides and nitrite in overweight/obese patients with schizophrenia  63 analyzed. sP-selectin was measured using ELISA 0.01 for exploratory analyses. All analyses were performed (Enzyme-linked immunosorbent assay) kits according in IBM SPSS, Version 24 (IBM Corp., Armonk, NY, USA). to the manufacturer’s (RayBiotech, Inc. Georgia, USA) instructions. Samples were diluted 1:50 after which optical density values for the samples were compared to Results standard curves ranging from 0-30ng/ml (Assay sensitivity was 20 pg/ml). Plasma TC, TG, LDL-C, and HDL-C were measured by Quest Diagnostics (Secaucus, NJ) using Sample characteristics spectrophotometry. hs-CRP was measured using an ELISA kit (MyBioSource, MBS703598); in preparation for The overall sample was approximately 33 years of age, on analysis, samples were diluted 1:1000 and the procedures average (M = 32.9, SD = 12.3), predominantly male (n = 76; were consistent with the manufacturer’s instructions. 71.6%), and a slight majority were African American (n = Plasma nitrite was measured following the protocol 55; 51.9%). Most participants had a high school diploma outlined by Giustarini and colleagues (2004) [21] using or equivalent (n = 38; 35.9%) at the time of the study. A a modified Griess-Ilosvay diazotization reaction assay slight majority of the sample had a BMI in the overweight/ (Merk KGaA, Darmstadt, Germany). The protocol included obese range (n = 54, 53.5%). Differences in plasma lipids the reaction of sulfanilamide with NO - present in samples between overweight/obese and normal weight patients acidified with phosphoric acid, forming a diazonium are reported elsewhere [19]. See Table 1 for a depiction of salt. N-(1-naphthyl) ethylenediamine dihydrochloride sample characteristics. is then coupled with the diazonium salt forming an azo dye which was subsequently analyzed at 562 nm in a spectrophotometer (KC4 reader, Bio-Tek Instruments, Inc., Association of sP-selectin with lipids and Winooski, VT, USA). The measurement of plasma NO - NO - in overweight/obese patients was carried out at the Division of Biological Chemistry, Biocenter, Medical University of Innsbruck, Austria. Results from unadjusted analyses indicated that sP-selectin was positively correlated with TG (r = 0.40, p < 0.01) and NO - (r = 0.38, p < 0.01), but had no Statistical Analyses significant correlation with TC, LDL-C, or HDL-C. The positive correlations between sP-selectin and TG and NO - Variables were first examined for normality. sP-selectin, respectively, remained significant after controlling for hs-CRP, and NO - were skewed to the right and a log potential confounders (r = 0.38, p = 0.01 and r = 0.40, p < transformation was performed on each variable. Means 0.01 respectively). See Table 2. ± standard deviation or percentages (as appropriate) are presented for descriptive variables. For sP-selectin, hs-CRP, and NO -, we have presented geometric means Association of sP-selectin with lipids and obtained by exponentiating the mean log-transformed NO - in the normal weight participants and in values. To examine the primary hypothesis that plasma the total sample sP-selectin is associated with plasma lipids and NO - in overweight/obese patients, Pearson’s correlations sP-selectin was not associated with plasma lipids or NO - were calculated with partial correlations to control for in either normal weight patients or in the total sample. potential confounders (i.e., sex, age, race, education and inflammation [i.e. hs-CRP]). On an exploratory basis, the correlations (Pearson’s and partial) of sP-selectin with Comparison of sP-selectin and NO - in plasma lipids and NO - were examined in the normal weight normal weight and overweight/obese patients and the entire sample (i.e., overweight/obese participants and normal weight combined). Exploratory analyses also included t-test to compare sP-selectin and NO - between sP-selectin and NO - did not differ between the normal 2 2 normal weight and overweight/obese patients. All tests weight and overweight/obese patients (43.35 ± 0.18 ng/ml were two-tailed. To control for type I error, Bonferroni vs. 38.02 ± 0.18 ng/ml, p=0.13 and; 21.44 ± 0.27 µmol/L vs. correction was applied in the primary analyses (i.e. in 24.14 ± 0.32 µmol/L, p=0.39 respectively) in this sample. overweight/obese patients only), while alpha was set at 64  Katelynn A. Bourassa et al. Table 1: Sociodemographic and metabolic characteristics of the Table 2: Correlations among sP-selectin, plasma lipids, and plasma sample (N = 106). nitrite in participants with BMI in the overweight/obese range (n = 54) before and after adjustment for sex, age, race, education, and hs-CRP. Variable Value Sex (Male; n [%]) 76 (71.60%) Pearson’s r p value Pearson’s r p value Mean Age ±SD 32.90 ±12.28 sP-selectin sP-selectin (unadjusted) (adjusted) Race n (%) TC 0.13 0.39 0.12 0.44 Caucasian 33 (31.10%) African American 55 (51.90%) TG 0.40 < 0.01 0.38 0.01 Hispanic 16 (15.10%) LDL-C 0.08 0.60 0.07 0.67 Asian 2 (1.90%) Education n (%) HDL-C -0.31 0.03 -0.31 0.04 No Degree 34 (32.10%) Plasma 0.38 < 0.01 0.40 < 0.01 High School/Equivalent 38 (35.90%) Nitrite Some College 25 (23.60%) HDL-C = High Density Lipoprotein Cholesterol; LDL-C = Low Density >2 Years College 9 (8.40%) Lipoprotein Cholesterol; r = correlation coefficient; TC = Total Mean BMI±SD 26.99±7.03 Cholesterol; TG = Triglycerides; n = 50 provided data for TC and HDL-C; n = 49 provided data for TG and LDL-C, n = 49 provided data BMI Category n (%) for plasma nitrite. Normal 47 (46.50%) Overweight/Obese 54 (53.50%) example, Belinski et al [22] found a positive correlation Geometric Mean sP-selectin (ng/ml) ±SD 40.08±0.18* between sP-selectin and both TG and LDL-C but a negative Geometric Mean hs-CRP (mg/L) ±SD 1.05±0.62* correlation with HDL-C in the Multi-Ethnic Study of Mean Total Cholesterol (mg/dL) ±SD 157.53±32.05 Atherosclerosis. Although we could not find any previous study Mean TG (mg/dL) ± SD 106.59 ± 56.89 involving patients with schizophrenia, research involving Mean LDL-C (mg/dL) ±SD 91.46±29.89 animals [23, 24] and non-psychiatric human participants Mean HDL-C (mg/dL) ±SD 44.75±14.40 [25–27] have related sP-selectin with NO - but they Geometric Mean Plasma Nitrite (µmol/L) ±SD 22.21±0.29* evaluated sP-selectin expression using other techniques (e.g. radiolabeled monoclonal antibody technique, Note. * = Geometric mean of log transformed variable; BMI = Body Western blot and flow cytometry) [24, 26, 27] rather than Mass Index; HDL-C = High Density Lipoprotein Cholesterol; hs-CRP = plasma levels as in our study. In the previous studies, High Sensitivity C-Reactive Protein; LDL-C = Low Density Lipoprotein there was a consistent finding of a negative correlation Cholesterol; sP-selectin = Soluble P-Selectin; TG = Triglycerides; 5 participants are missing BMI data between sP-selectin and NO - (as well as nitrate [NO -]). For 2 3 example, exogenously administered NO - (e.g. dietary NO - 2 2 ) attenuated P-selectin [28–30] while inhibition of NO (and Discussion therefore NO - and NO -) biosynthesis increased P-selectin 3 2 expression [26, 27]. Contrary to previous studies and We found, for the first time (to our knowledge), a our hypothesis, we found a positive correlation between positive correlation between sP-selectin and both TG sP-selectin and NO - in the subsample of overweight/ and NO - respectively in overweight/obese patients obese patients with schizophrenia after controlling for with schizophrenia but not in normal weight patients; potential confounding factors. A plausible explanation however, we did not observe any association between (though speculative) for our finding is that NO synthesis sP-selectin and TC, LDL-C, or HDL-C. Our finding of increases in parallel with sP-selectin in overweight/obese a positive relationship between sP-selectin and TG in patients as an attempt to counteract the procoagulant overweight/obese adults with schizophrenia is consistent and atherogenic effects of sP-selectin and the atherogenic with the limited literature in non-psychiatric samples. For effect of TG. It is also possible that the expression of iNOS Plasma soluble P-selectin correlates with triglycerides and nitrite in overweight/obese patients with schizophrenia  65 is increased in the overweight/obese patients since iNOS factors confounded, mediated, or moderated the observed expression is increased in obesity-induced inflammatory associations among sP-selectin, TG, and NO as suggested 2- states [31] and as described earlier, levels of inflammation by prior research reporting sP-selectin elevation in the were higher in the overweight/obese patients [19]. It is, aforementioned conditions [39, 40]. however, important to note that there was no difference in NO - levels between overweight/obese patients and normal-weight patients in this sample. Future directions Regarding the association of sP-selectin with TG in the overweight/obese patients, it is plausible to speculate The utility of sP-selectin as a potential biomarker of that it could be an indication of ensuing pathology in cardiovascular health in overweight/obese patients with the vasculature related to the combination of elevated schizophrenia should be evaluated in future prospective inflammation and hypertriglyceridemia in the overweight/ cohort studies by serial measurements of sP-selectin, obese patients [19]. This inference is consistent with the lipids, NO -, and relating them to the incidence of report of a systemic inflammatory environment inducing cardiovascular events (e.g. myocardial infarction and a phenotypic switch to a proatherogenic endothelium stroke). Other studies should also evaluate the efficacy of which leads to enhanced expression of P-selectin [32, dietary nitrite and nitrate supplementation in overweight/ 33]. The potential importance of our observed association obese patients with schizophrenia since dietary nitrite is also highlighted by the fact that recent data suggest and nitrate have been shown to increase bioavailability of that when standardized for their respective effects on NO and decrease triglyceride levels in a non-psychiatric apolipoprotein B (ApoB), TG might confer similar risk of sample [41]. Furthermore, in experimental models, CVD as LDL-C, an established CVD risk factor [34, 35]. dietary nitrite and nitrate supplementation attenuate However, we did not observe higher levels of sP-selectin the metabolic abnormalities (obesity, hyperlipidemia, in the overweight/obese patients relative to normal weight glucose intolerance, inflammation and oxidative stress) patients, a finding that is inconsistent with the preceding induced by high-fat diet in mice [42]. The effect of weight arguments and requires further exploration. loss interventions on sP-selectin and its association with Several limitations should be considered when lipids and NO -, might be also evaluated in future studies interpreting the findings of the current study. First, the since in non-psychiatric samples obese individuals who average BMI in our study population was at the lower lost 10% (or more) of their body weight in six months end of the overweight category (i.e., 26.99±7.03 kg/m ), exhibited reductions in endothelial dysfunction and and it is possible that the relationship among sP-selectin platelet activation as evidenced by platelet aggregation and plasma TG and NO - may be stronger in a more obese studies and reduced sP-selectin levels [43]. population. Additionally, average plasma lipid levels were In addition, longitudinal studies of medication naïve within the normal range for the total sample, which may patients are necessary to take into account the metabolic have resulted in an attenuated relationship with sP-selectin. effects of neuroleptics [44] as well as their potential effect Second, given the cross-sectional study design, causal on vascular dysfunction [45]. Finally, collecting larger relationships among sP-selectin, NO -, TG, overweight/ samples with greater variability in BMI status would allow obesity, cannot be established and the findings of this for a more in-depth examination of the relationships study may not generalize to other populations. Third, data among sP-selectin, plasma lipids, and NO in adults with on psychotropic medication type and dosage, important schizophrenia who have BMIs in the normal, overweight, potential confounders, were not available for this study. and obese ranges. As the affinity for weight gain differs among neuroleptics [36], we were unable to evaluate whether neuroleptics may differentially impact the relationship among Acknowledgements: Dr. Postolache’ s contribution to sP-selectin, NO -, and TG in adults with schizophrenia. this study was supported by a NORC exploratory grant (PI, Fourth, dietary sources contribute considerably to Postolache, co PI Snitker), offspring of the parent grant plasma NO - and NO - [37, 38] but since we did not collect P30 DK072488, from the NIDDK/NIH. 3 2 information on dietary intake, the possibility that our results are related to diet, cannot be ruled out. Finally, we Conflict of interest: Prof. Fuchs is Editor-in-Chief of did not collect data regarding additional CVD risk factors Pteridines. (e.g., smoking status, metabolic syndrome, diabetes). We were unable to determine whether the presence of these 66  Katelynn A. Bourassa et al. syndrome in the Old Order Amish. 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Journal

Pteridinesde Gruyter

Published: Jan 1, 2020

Keywords: schizophrenia; overweight/obesity; P-selectin; nitrite; atherosclerosis

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