افسردگی اساسی باعث استرس اکسیداتیو و تجمع بیش از حد پلاکت می شود
|کد مقاله||سال انتشار||مقاله انگلیسی||ترجمه فارسی||تعداد کلمات|
|29807||2015||6 صفحه PDF||سفارش دهید||محاسبه نشده|
Publisher : Elsevier - Science Direct (الزویر - ساینس دایرکت)
Journal : Journal of Psychiatric Research, Volume 61, February 2015, Pages 19–24
We have previously demonstrated an impairment of intraplatelet l-arginine-nitric oxide-cGMP pathway in major depression (MD) associated to platelet dysfunction. Here, we evaluated arginase pathway and phosphodiesterase 5 (PDE5) expression in platelets, systemic and intraplatelet oxidative status in untreated MD patients, and their effects on platelet aggregation. Blood samples were collected from 22 treatment naive MD patients (31 ± 2 yr) and 27 healthy subjects (33 ± 2 yr). MD patients presented with an activation of platelet arginase II, which competes with l-arginine for the production of nitric oxide (NO). An increase in protein carbonylation, overexpression of NADPH oxidase and PDE5, an enzyme that inactivates cGMP, was observed in platelets from MD patients compared to controls. In this context, platelet hyperaggregability was found in MD patients. On the other hand, antioxidant enzymes catalase, glutathione peroxidase and superoxide dismutase activities in serum and in platelets did not differ between groups. The increased activation of intraplatelet arginase and platelet aggregability, in addition to an overexpression of PDE5 and oxidative stress may contribute to alterations in l-arginine–NO–cGMP pathway and in platelet function, and consequently to the increased thrombotic risk in MD.
Major depression (MD) is considered an independent risk factor for cardiovascular disease (CVD), and depressed patients with pre-existing CVD also present an increased mortality risk (Baghai et al., 2011, Brown et al., 2009, Chrapko et al., 2004, Pinto et al., 2008 and Roose, 2000). To date, the exact mechanisms linking MD and CVD are not well known. It has been suggested that nitric oxide (NO) bioavailability or abnormalities in its signaling pathways may be involved in the occurrence of cardiovascular events in psychiatric diseases (Chrapko et al., 2004, Le Melledo et al., 2004 and Pinto et al., 2008). NO is a potent vasodilator and inhibitor of platelet function, and its synthesis occurs through the conversion of the amino acid l-arginine to l-citrulline and NO by a family of enzymes known as nitric oxide synthase (NOS) (Brunini et al., 2007 and Mendes Ribeiro et al., 1999). The majority of NO effects occur through a highly regulated interplay of cGMP formation by NO-induced activation of soluble guanylyl cyclase (sGC) and its degradation by phosphodiesterases (PDE), particularly PDE 5 (Berkels et al., 2001 and Brunini et al., 2007). The cationic amino acid l-arginine is also involved in the urea cycle. It is a substrate for arginase, which hydrolyzes l-arginine into l-ornithine and urea (Mendes Ribeiro et al., 1999 and Pereira et al., 2010). Two arginase isoforms have been described: arginase I, present in cytosol, and arginase II, present in mitochondria, but only arginase II has been detected in human platelets (Mendes Ribeiro et al., 1999 and Pereira et al., 2010). As arginase competes with NOS for l-arginine, changes in arginase activity can affect NO bioavailability. Moreover, l-ornithine is the principal precursor for production of polyamines required for cell proliferation and differentiation, which is a main feature of atherosclerotic lesions and restenosis (Forte et al., 2011). Oxidative stress is one of the major factors known to reduce NO bioavailability (Valko et al., 2007). It is described as an imbalance between reactive oxygen species (ROS) generation and the biological ability of the body to neutralize them, by means of enzymatic and non-enzymatic antioxidant defence mechanisms. The major antioxidant enzymes include copper–zinc superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx), while non-enzymatic antioxidants include bilirubin, uric acid, glutathione, and vitamins A, C, and E (Valko et al., 2007). On the other hand, ROS generation occurs through mechanisms mainly involving NADPH oxidases in the vascular system and in blood cells (Bedard and Krause, 2007). Excessive ROS production, namely superoxide anion, is likely to increase quenching of NO and to activate platelets. Moreover, ROS have direct effect in all stages of platelet activation (Bedard and Krause, 2007), and to our knowledge, there is no report of the oxidative status in platelets from patients with MD. Platelets are an essential component of the hemostatic process, which happens as follows. In brief, mechanical disruption of blood vessels initiates localized hemostatic responses involving interactions of vascular endothelium, platelets, red blood cells, coagulation and fibrinolysis (Fig. 1). Platelet thrombus formation involves three main steps: platelet adhesion to the damaged endothelium, its activation, and aggregation. Platelet activation involves the generation of intracellular chemical signals that are initiated by platelets through specific surface receptors (e.g. integrins). These signals cause dramatic morphological changes such as the extension of pseudopodia, platelet–platelet aggregation, and granule secretion (e.g. adenosine diphosphate, tromboxane A2, serotonin), resulting in the generation of platelet thrombus [for an excelent detailed review, please refer to Versteeg et al. (2013)]. Supporting the importance of platelet-dependent thrombosis, the inhibition of platelet activation and aggregation is a common therapeutic target for the acute treatment and secondary prevention of ischemic events (Franchi and Angiolillo, 2015). Platelet dysfunction is a possible mechanism through which depression may increase cardiovascular risk (Celano and Huffman, 2011). In fact, patients with depression have more circulating platelet-leukocyte aggregates compared to controls, indicating a heightened level of platelet activation, which was demonstrated to be directly associated with the severity of depression (Morel-Kopp et al., 2009). In addition, our group has previously demonstrated increased platelet aggregation induced by ADP, associated with an inhibition of intraplatelet l-arginine-NO pathway in patients with MD and bipolar disorder (Fontoura et al., 2012 and Pinto et al., 2012). Full-size image (27 K) Fig. 1. Platelets during the formation of platelet plug in hemostasis. Figure options In the present study, we aimed to improve the biological understanding of the factors that modulate NO bioavailability and platelet dysfunction. Therefore, it was assessed oxidative status, platelet aggregation, arginase pathway and phosphodiesterase 5 expression in platelets from untreated young adults with MD. Biomarkers of oxidative stress were also assessed in serum.
نتیجه گیری انگلیسی
As shown in Table 1, there were no significant differences in important demographic (age) and clinical data (BMI, lipid and glucose levels, and blood pressure) between MD patients and healthy control subjects. Table 1. Demographical and clinical data of MD patients and controls. Control group (n = 27) MD group (n = 22) Age (years) 33 ± 2 31 ± 2 Gender (M/F) 10/17 4/18 Ethnicity (white/non-white, %) 94/6 94/6 BMI (kg/m2) 23.4 ± 0.7 22.6 ± 0.5 RBC (106/mm3) 5.0 ± 0.2 4.3 ± 0.1* Leukocytes (103/mm3) 6.0 ± 0.3 6.6 ± 0.5 Hematocrit (%) 42.0 ± 0.7 40.0 ± 0.7 Hemoglobin (g/dL) 14.0 ± 0.2 13.0 ± 0.3 Platelets (103/mm3) 210 ± 11 230 ± 9 HDL Cholesterol (mg/dL) 52 ± 3 58 ± 4 LDL Cholesterol (mg/dL) 100 ± 7 100 ± 5 Triglycerides (mg/dL) 87 ± 8 96 ± 13 Glucose (mg/dL) 87 ± 2 83 ± 2 Sodium (mmol/L) 140 ± 0.5 140 ± 0.8 Potassium (mmol/L) 4.2 ± 0.0 4.4 ± 0.2 Creatinine (mmol/L) 0.88 ± 0.04 0.75 ± 0.03** Urea (mmol/L) 30 ± 1.7 28 ± 1.6 Albumin (g/dL) 4.6 ± 0.1 4.4 ± 0.07 Systolic blood pressure (mmHg) 110 ± 2 110 ± 2 Diastolic blood pressure (mmHg) 72 ± 2 70 ± 2 Data are show as mean ± SD. HDL, high density lipoprotein; LDL, low density lipoprotein. *P = 0.012 **P = 0.022. Table options 3.2. Platelet aggregation A significant increased level of ADP-induced platelet aggregation was found in MD group in comparison to healthy control group (P = 0.041) ( Fig. 2). Full-size image (11 K) Fig. 2. Platelet aggregation from MD patients and controls. Values denote mean ± SD*Different from control group (P = 0.041). Figure options 3.3. Arginase II activity and PDE5 expression in platelets Basal activity of arginase II (Fig. 3), assessed in platelet lysates by the conversion of [14C]-l-arginine into [14C]-urea, was significantly increased in patients with MD compared to healthy controls (P = 0.024). It was also observed that MD patients presented increased levels of PDE5 protein expression compared to healthy control subjects ( Fig. 4, P = 0.048). Full-size image (12 K) Fig. 3. Activity of arginase II in platelets from MD patients and controls. Values denote mean ± SD*Different from control group (P = 0.024).