Lipid Oxidation Products and the Risk of Cardiovascular Diseases: Role of Lipoprotein Transport.

Cholesterol has for decades ruled the history of atherosclerotic cardiovascular diseases (CVDs), and the present view of the etiology of the disease is based on the transport of cholesterol by plasma lipoproteins. The new knowledge of the lipoprotein-specific transport of lipid oxidation products (LOPs) has introduced another direction to the research of CVD, revealing strong associations between lipoprotein transport functions, atherogenic LOP, and CVD. The aim of this review is to present the evidence of the lipoprotein-specific transport of LOP and to evaluate the potential consequences of the proposed role of the LOP transport as a risk factor. The associations of cholesterol and lipoprotein LOP with the known risk factors of CVD are mostly parallel, and because of the common transport and cellular intake mechanisms it is difficult to ascertain the independent effects of either cholesterol or LOP. While cholesterol is known to have important physiological functions, LOPs are merely regarded as metabolic residues and able to initiate and boost atherogenic processes. It is therefore likely that with the increased knowledge of the lipoprotein-specific transport of LOP, the role of cholesterol as a risk factor of CVD will be challenged.

The associations of oxidized lipoprotein lipids with lipoprotein subclass particle concentrations and their lipid compositions. The Cardiovascular Risk in Young Finns Study.

OBJECTIVE: Oxidation of low-density lipoprotein (LDL) may promote atherosclerosis, whereas the reverse transport of oxidized lipids by high-density lipoprotein (HDL) may contribute to atheroprotection. To provide insights into the associations of lipoprotein lipid oxidation markers with lipoprotein subclasses at the population level, we investigated the associations of oxidized HDL lipids (oxHDLlipids) and oxidized LDL lipids (oxLDLlipids) with lipoprotein subclasses in a population-based cross-sectional study of 1395 Finnish adults ages 24-39 years. METHODS: The analysis of oxidized lipids was based on the determination of the baseline level of conjugated dienes in lipoprotein lipids. A high-throughput nuclear magnetic resonance (NMR) platform was used to quantify circulating lipoprotein subclass concentrations and analyze their lipid compositions. RESULTS: OxHDLlipids were mainly not associated with lipoprotein subclass lipid concentrations and lipid composition after adjustment for Apolipoprotein-A1 (Apo-A1), waist circumference and age. OxLDLlipids were associated with several markers of lipoprotein subclass lipid concentrations and composition after adjustment for Apolipoprotein-B (Apo-B), age and waist circumference. Several measures of HDL and LDL subclasses, including phospholipid and triglyceride composition, associated directly with oxLDLlipids. Cholesterol ester and free cholesterol composition in HDL and LDL associated inversely with oxLDLlipids. CONCLUSION: We conclude that these results do not support the idea that HDL's particle size or composition would reflect its functional capacity in the reverse transport of oxidized lipids. On the contrary, oxLDLlipids were associated with the entire lipoprotein subclass profile, including numerous associations with the compositional descriptors of the particles. This is in line with the suggested role of LDL oxidation in atherogenesis.

The metabolic syndrome in mice overexpressing neuropeptide Y in noradrenergic neurons.

A gain-of-function polymorphism in human neuropeptide Y (NPY) gene (rs16139) associates with metabolic disorders and earlier onset of type 2 diabetes (T2D). Similarly, mice overexpressing NPY in noradrenergic neurons (OE-NPYDBH) display obesity and impaired glucose metabolism. In this study, the metabolic syndrome-like phenotype was characterized and mechanisms of impaired hepatic fatty acid, cholesterol and glucose metabolism in pre-obese (2-month-old) and obese (4-7-month-old) OE-NPYDBH mice were elucidated. Susceptibility to T2D was assessed by subjecting mice to high caloric diet combined with low-dose streptozotocin. Contribution of hepatic Y1-receptor to the phenotype was studied using chronic treatment with an Y1-receptor antagonist, BIBO3304. Obese OE-NPYDBH mice displayed hepatosteatosis and hypercholesterolemia preceded by decreased fatty acid oxidation and accelerated cholesterol synthesis. Hyperinsulinemia in early obese state inhibited pyruvate- and glucose-induced hyperglycemia, and deterioration of glucose metabolism of OE-NPYDBH mice developed with aging. Furthermore, streptozotocin induced T2D only in OE-NPYDBH mice. Hepatic inflammation was not morphologically visible, but upregulated hepatic anti-inflammatory pathways and increased 8-isoprostane combined with increased serum resistin and decreased interleukin 10 pointed to increased NPY-induced oxidative stress that may predispose OE-NPYDBH mice to insulin resistance. Chronic treatment with BIBO3304 did not improve the metabolic status of OE-NPYDBH mice. Instead, downregulation of beta-1-adrenoceptors suggests indirect actions of NPY via inhibition of sympathetic nervous system. In conclusion, changes in hepatic fatty acid, cholesterol and glucose metabolism favoring energy storage contribute to the development of NPY-induced metabolic syndrome, and the effect is likely mediated by changes in sympathetic nervous system activity.

Oxidized lipoprotein lipids and atherosclerosis.

Plasma lipoproteins contain variable amounts of lipid oxidation products (LOP), which are known to impair normal physiological functions and stimulate atherosclerotic processes. Recent evidence indicates that plasma lipoproteins are active carriers of LOP, low-density lipoprotein (LDL) directing transport toward peripheral tissues, and high-density lipoprotein (HDL) being active in the reverse transport. It has been proposed that the lipoprotein-specific transport of LOP could play a role in atherosclerosis-related effects of LDL and HDL. This article gives an overview of the present knowledge of lipoprotein LOP transport and its association with the risk of atherosclerosis and cardiovascular diseases (CVD). Evidence of the significance of lipoprotein LOP transport comes mainly from studies of physiological oxidative stress and is supported by studies of the functionality apolipoprotein A-1 mimetic peptides. A large body of data has accumulated indicating that lipoprotein LOP transport is connected to the risk of atherosclerosis. While high levels of LOP carried by LDL are indicative of elevated risk, high LOP level in HDL appears to associate with protection. If confirmed, the proposed lipoprotein LOP transport function would affect conception of the etiology of atherosclerosis, but would not conflict current views of the pathophysiological mechanisms. It could open new perspectives, such as the dietary origin of LOP, and the protective function of HDL in clearance of LOP. Focusing on LOP could give additional tools especially for prevention and diagnosis, but would not radically change the management of atherosclerosis and CVD.

Two weeks of moderate-intensity continuous training, but not high-intensity interval training, increases insulin-stimulated intestinal glucose uptake.

Similar to muscles, the intestine is also insulin resistant in obese subjects and subjects with impaired glucose tolerance. Exercise training improves muscle insulin sensitivity, but its effects on intestinal metabolism are not known. We studied the effects of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on intestinal glucose and free fatty acid uptake from circulation in humans. Twenty-eight healthy, middle-aged, sedentary men were randomized for 2 wk of HIIT or MICT. Intestinal insulin-stimulated glucose uptake and fasting free fatty acid uptake from circulation were measured using positron emission tomography and [18F]FDG and [18F]FTHA. In addition, effects of HIIT and MICT on intestinal GLUT2 and CD36 protein expression were studied in rats. Training improved aerobic capacity (P = 0.001) and whole body insulin sensitivity (P = 0.04), but not differently between HIIT and MICT. Insulin-stimulated glucose uptake increased only after the MICT in the colon (HIIT = 0%; MICT = 37%) (P = 0.02 for time × training) and tended to increase in the jejunum (HIIT = -4%; MICT = 13%) (P = 0.08 for time × training). Fasting free fatty acid uptake decreased in the duodenum in both groups (HIIT = -6%; MICT = -48%) (P = 0.001 time) and tended to decrease in the colon in the MICT group (HIIT = 0%; MICT = -38%) (P = 0.08 for time × training). In rats, both training groups had higher GLUT2 and CD36 expression compared with control animals. This study shows that already 2 wk of MICT enhances insulin-stimulated glucose uptake, while both training modes reduce fasting free fatty acid uptake in the intestine in healthy, middle-aged men, providing an additional mechanism by which exercise training can improve whole body metabolism.NEW & NOTEWORTHY This is the first study where the effects of exercise training on the intestinal substrate uptake have been investigated using the most advanced techniques available. We also show the importance of exercise intensity in inducing these changes.

6-mo aerobic exercise intervention enhances the lipid peroxide transport function of HDL.

During acute exercise, the concentration of oxidized high-density lipoprotein (HDL) lipids (ox-HDL) is reported to increase suggesting that HDL may function in decreasing the concentration of oxidized low-density lipoprotein (LDL) lipids. However, the effect of exercise intervention on the lipid peroxide transport function of HDL is unknown. A randomized controlled trial with sedentary women (N = 161), aged 43-63, with no current use of hormone therapy, were randomized into a 6-month (mo) exercise group and a control group. During the 6-mo intervention, the concentration of ox-HDL increased in the exercise group by 5% and decreased in the control group by 2% (p = .003). Also, the ratio of ox-HDL to HDL-cholesterol increased by 5% in the exercise group and decreased by 1.5% in the control group (p = .036). The concentrations of cholesteryl ester transfer protein (CETP) and adiponectin did not change during the intervention. The concentration of serum triglycerides trended to decrease by 6% in the intervention group (p = .051). We found that the concentration of ox-HDL increased during the 6-mo aerobic exercise intervention, but the increase was not related to changes in the levels of CETP or adiponectin. These results, together with earlier studies, suggest that HDL has an active role in the reverse transport of lipid peroxides.

Increased Oxidative Stress in the Proximal Stomach of Patients with Barrett's Esophagus and Adenocarcinoma of the Esophagus and Esophagogastric Junction.

OBJECTIVES: Oxidative stress (OS) is an essential element in the pathogenesis of Barrett's esophagus (BE) and its transformation to adenocarcinoma (EAC). The state of OS in the proximal stomach of patients with BE and EAC is unknown. Isoprostanes are a specific marker of OS not previously used to determine OS from BE/EAC tissue samples. PATIENTS AND METHODS: OS was measured in 42 patients with BE (n = 9), EAC (n = 9), or both (n = 24) and 15 control patients. A STAT-8-Isoprostane EIA Kit served to identify 8-Isoprostanes (8-IP), and a Glutathione Assay Kit was used to measure glutathione reduced form (GSH) and glutathione oxidized form. An OxiSelect Oxidative DNA Damage ELISA Kit (8-OHdG) served to measure 8-OH-deoxyguanosine. RESULTS: The 8-IP (P = .039) and 8-OHdG (P = .008) levels were higher, and the GSH level lower (P = .031), in the proximal stomach of the study group than in that of the controls. Helicobacter pylori infection was present in 8% of the study patients. CONCLUSIONS: In the proximal stomach of BE and EAC patients, OS was elevated and antioxidative capacity was reduced. This finding suggests that the gastroesophageal reflux causing BE also induces oxidative stress in the proximal stomach and may contribute to the development of cancer in the proximal stomach and gastric cardia.

Strenuous physical exercise accelerates the lipid peroxide clearing transport by HDL.

PURPOSE: Physical exercise has cardioprotective functions, which have been partly linked to high-density lipoprotein (HDL), and its functions. We studied the effects of endogenous oxidative stress, induced by acute exhaustive physical exercise, on concentration of oxidized HDL lipids. METHODS: Twenty-four male national top-level endurance runners, 12 middle-distance runners and 12 marathon runners performed a maximal run on a treadmill until exhaustion. We analyzed concentrations of oxidized HDL (oxHDLlipids) and LDL lipids (oxLDLlipids), serum antioxidant potential (TRAP), paraoxonase activity and malondialdehyde. Venous blood samples were taken before, immediately, 15 and 90 min after exercise. RESULTS: Immediately after the treadmill run the concentration of oxHDLlipids was increased by 24 % (p < 0.01). Simultaneously, the ratio of oxHDLlipids to oxLDLlipids increased by 55 % and the oxLDLlipids levels decreased by 19 % (p < 0.001), while serum malondialdehyde and TRAP increased by 54 % (p < 0.001) and 29 % (p < 0.01), respectively. After the 90 min recovery the concentration of oxHDLlipids was decreased towards the pre-exercise level, but that of oxLDLlipids remained decreased below pre-exercise values (p < 0.001). The change in oxLDLlipids after the run correlated positively with VO2max (r = 0.67, p < 0.001) and negatively with the change in paraoxonase activity (r = -0.47, p < 0.05). CONCLUSIONS: We conclude that acute exhaustive physical exercise increased the concentration of oxHDLlipids and decreased that of oxLDLlipids and the ratio of oxLDLlipids to oxHDLlipids, which suggests that during physical exercise HDL has an active role in the removal of lipid peroxides.

Longitudinal study of circulating oxidized LDL and HDL and fatty liver: the Cardiovascular Risk in Young Finns Study.

Oxidative reactions are thought to play a role in the inflammatory condition called fatty liver. It is unclear whether oxidized lipoprotein lipids or proteins are associated with future fatty liver. In the Cardiovascular Risk in Young Finns Study, we determined the circulating levels of LDL and HDL oxidized lipids and studied their associations with fatty liver assessed by ultrasonography. There were 1286 middle-aged subjects with normal liver and 288 subjects with fatty liver. Analysis of oxidized lipids consisted of conjugated dienes in isolated HDL (oxHDLlipids) and LDL (oxLDLlipids). Oxidized LDL was also measured with a method based on antibodies against oxidized apolipoprotein B (oxLDLprot). After adjustment for age, sex, leisure-time physical activity, body mass index, alcohol intake, smoking, serum LDL and HDL cholesterol as well as particle concentrations, participants with elevated oxLDLlipids (odds ratio for 1-SD change in oxLDLlipids = 1.27, p =0.011) had an increased risk for fatty liver. Similarly, a high oxidation score (oxLDLlipids + oxLDLprot) was directly associated with fatty liver (odds ratio=1.34, p = 0.012). The strongest direct association was seen with a high oxLDLlipids/oxHDLlipids ratio (odds ratio=1.49, p = 0.001). These data suggest that oxidized lipoprotein lipids are linked with the risk of fatty liver in middle-aged adults.

Co-existence of insulin resistance and high concentrations of circulating oxidized LDL lipids.

INTRODUCTION: Insulin metabolism has been previously linked to oxidized low-density lipoproteins (ox-LDL), but corroborating intervention studies are lacking. We investigated whether changes in ox-LDL levels are accompanied by changes in insulin sensitivity in a 32-month life-style intervention study. MATERIALS AND METHODS: A 2-month weight reduction was followed by 6-month diet and exercise counselling and a 2-year follow-up period. Men of 35-50 years of age, BMI ≥ 30 kg/m(2), and waist circumference > 100 cm were recruited via newspapers in the city of Tampere, Finland. Of the 90 men meeting the inclusion criteria, 67 (76%) completed the study. Ox-LDL was estimated as the presence of oxidized lipids in LDL. Homeostasis model assessment of insulin resistance (HOMA-IR), ox-LDL, and ratio of ox-LDL and high-density lipoprotein cholesterol (ox-LDL/HDL-c) were used as the main outcome measures. RESULTS: The detected changes in HOMA-IR were strikingly similar to those in ox-LDL and ox-LDL/HDL-c. Compared to the first HOMA-IR quartile, the fourth quartile had 23%-51% higher concentrations in ox-LDL and ox-LDL/HDL-c at all time points (P < 0.05 for all). CONCLUSION: This weight reduction intervention study adds evidence to support the connection between insulin metabolism and oxidized LDL, possibly contributing to the higher incidence of atherosclerotic cardiovascular diseases among diabetic patients.

Paraoxonase-1 and oxidized lipoprotein lipids. The Cardiovascular Risk in Young Finns Study.

OBJECTIVE: Paraoxonase-1 (PON1) is suggested to have a role in the antioxidant activity of high-density lipoprotein (HDL). PON1 activity levels are strongly genetically determined by the rs662 polymorphism (PON1 Q192R). To clarify the role of PON1 in lipoprotein oxidation at the population level, we examined the relations between PON1 activity, the rs662 polymorphism and oxidized lipoprotein lipids in young adults. METHODS: A population-based cross-sectional study of 1895 Finnish adults ages 24-39 years (872 males and 1023 females). PON1 activity was determined with paraoxon as the substrate. Analysis of oxidized lipids in isolated HDL (oxHDLlipids) and low-density lipoprotein (oxLDLlipids) was based on the determination of conjugated dienes. Oxidized LDL was also measured with a method based on antibodies against oxidized Apo-B (oxLDLprot). Serum lipids and apolipoproteins were measured. Genotyping was performed with the Illumina Bead Chip (Human 670 K). RESULTS: In multivariable models, PON1 activity associated inversely with oxLDLlipids (p = 0.0001, semi-partial R(2) = 0.09%), but it was not associated with oxHDLlipids (p = 0.93). There was a borderline significant association between PON1 activity and oxLDLprot (p = 0.08). PON1 rs662 polymorphism was strongly associated with PON1 activity (P-value<0.0001), but not with oxidized lipoprotein lipids and oxLDLprot. CONCLUSION: Higher PON1 activity is associated with decreased oxLDLlipids levels, but not with oxHDLlipids in a population of young Finnish adults. These findings support the suggestion that PON1 activity may have a role in the oxidation of LDL lipids. There is a strong association between PON1 rs662 polymorphism and PON1 activity, but PON1 rs662 polymorphism is not associated with oxidized lipoprotein lipids and oxLDLprot.

The impact of beef steak thermal processing on lipid oxidation and postprandial inflammation related responses.

Oxidised lipid species, their bioavailability and impact on inflammatory responses from cooked beef steak are poorly characterised. Oxidised lipid species from pan-fried (PF) and sous-vide (SV) thermally processed beef were determined with UHPLC-ESI/MS. Twenty-three lipid oxidation products increased with thermal processing and differences between the PF and SV steaks were measured. Fifteen oxidised lipids were measured in post-meal plasma after a cross-over randomised clinical study. Postprandial plasma inflammatory markers tended to remain lower following the SV meal than the PF meal. High levels of conjugated dienes were measured in the HDL fraction, suggesting that the protective effect of HDL may extend to the reverse-transport of oxidised lipid species. Oxidised lipids in a single meal may influence postprandial oxidative stress and inflammation. Further studies are required to examine the lipid oxidative responses to increased dietary oxidative lipid load, including the reverse transport activity of HDL.

Postprandial triglyceride response in normolipidemic, hyperlipidemic and obese subjects - the influence of polydextrose, a non-digestible carbohydrate.

BACKGROUND: Three independent trials were conducted to evaluate postprandial triglyceride (TG) responses in subjects with different lipid metabolism. The effect of polydextrose (PDX), a soluble non-digestible carbohydrate, on postprandial response was also studied using practically relevant, high fat meal interventions. METHODS: A total of 19 normolipidemic (average BMI 24.1 kg/m(2)), 21 overweight/hyperlipidemic (average BMI 29.6 kg/m(2)) and 18 obese/non-diabetic subjects (average BMI 33.6 kg/m(2)) were included in the study. On two separate occasions all subjects ate two high-fat meals (4293 kJ, 36% from fat), one with PDX (either 12.5 g or 15 g) and one without PDX during placebo-controlled, double-blind, crossover and randomized trials. To obtain the triglyceride measurements venous blood samples were taken before the consumption of the test meal and five times afterwards, up to 6 h post-test meal. The triglyceride responses were modeled using a mixed-effects linear model. RESULTS: The key variables that explain the variation of the postprandial triglyceride response in the different subject groups were: baseline triglyceride concentration, time point, and PDX vs. placebo treatment (p < 0.05). The maximum postprandial TG concentration was more pronounced in hyperlipidemic group compared to normolipidemic (p < 0.001) or obese groups (p < 0.01). The modeled TG response analysis showed that irrespective of the study population PDX supplementation was one of the factors significantly reducing triglyceride response compared to the placebo treatment (p < 0.05). CONCLUSIONS: Subjects with elevated fasting triglyceride levels display exaggerated and prolonged postprandial triglyceride responses. PDX, a soluble non-digestible carbohydrate, may offer a dietary concept for reducing the postprandial triglyceride response after the consumption of a meal containing a high concentration of fat.

High density lipoprotein level is negatively associated with the increase of oxidized low density lipoprotein lipids after a fatty meal.

Recent reports show that a fatty meal can substantially increase the concentration of oxidized lipids in low density lipoprotein (LDL). Knowing the LDL-specific antioxidant effects of high density lipoprotein (HDL), we aimed to investigate whether HDL can modify the postprandial oxidative stress after a fatty meal. Subjects of the study (n = 71) consumed a test meal (a standard hamburger meal) rich in lipid peroxides, and blood samples were taken before, 120, 240, and 360 min after the meal. The study subjects were divided into four subgroups according to the pre-meal HDL cholesterol value (HDL subgroup 1, 0.66-0.91; subgroup 2, 0.93-1.13; subgroup 3, 1.16-1.35; subgroup 4, 1.40-2.65 mmol/L). The test meal induced a marked postprandial increase in the concentration of oxidized LDL lipids in all four subgroups. The pre-meal HDL level was associated with the extent of the postprandial rise in oxidized LDL lipids. From baseline to 6 h after the meal, the concentration of ox-LDL increased by 48, 31, 24, and 16% in the HDL subgroup 1, 2, 3, and 4, respectively, and the increase was higher in subgroup 1 compared to subgroup 3 (p = 0.028) and subgroup 4 (p = 0.0081), respectively. The pre-meal HDL correlated with both the amount and the rate of increase of oxidized LDL lipids. Results of the present study show that HDL is associated with the postprandial appearance of lipid peroxides in LDL. It is therefore likely that the sequestration and transport of atherogenic lipid peroxides is another significant mechanism contributing to cardioprotection by HDL.

Delay in rat lung alveolarization after the combined exposure of maternal hyperglycemia and postnatal hyperoxia.

BACKGROUND: Maternal diabetes interferes with fetal lung development and postnatal treatments may further disturb pulmonary growth. Therefore, we investigated the effect of postnatal oxygen exposure on alveolar development in neonatal rat lungs pre-exposed to intrauterine hyperglycemia. METHODS: Diabetes was induced in Sprague-Dawley rats with streptozotocin injection before pregnancy. Hyperglycemia-exposed and control litters were randomized to breath room air or 85% oxygen for 7 days after birth. Lungs were analyzed on postnatal d7 for weight, morphology, apoptosis, proliferation, and biomarkers of oxidative stress. RESULTS: Maternal hyperglycemia accelerated lung development as demonstrated by thinner alveolar walls and slightly increased secondary septation when compared to room air bred rats. Hyperoxia alone caused thin-walled and enlarged alveoli with few secondary septa. Interestingly, the dual exposure inhibited the thinning of alveolar walls and the disappearance of mesenchymal cells from the alveolar walls together with the delay in the formation of alveoli and secondary crests. While the lungs' oxidative stress was similar in all groups, pulmonary apoptosis and proliferation were altered. CONCLUSION: Our results thus indicate that the hyperglycemic priming of the fetal lung modifies the deleterious effect of hyperoxia on alveolarization in neonatal rats.

Postpartum weight retention is associated with elevated ratio of oxidized LDL lipids to HDL-cholesterol.

Oxidized LDL lipids (ox-LDL) are associated with lifestyle diseases such as cardiovascular diseases, metabolic syndrome and type 2 diabetes. The present study investigated how postpartum weight retention effects on ox-LDL and serum lipids. The study is a nested comparative research of a cluster-randomized controlled trial, NELLI (lifestyle and counselling during pregnancy). During early pregnancy (8-12 weeks) and 1 year postpartum, 141 women participated in measurements for determining of plasma lipids: total cholesterol (T-C), LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C), triacylglycerols (TAG) and ox-LDL. Subjects were stratified into tertiles (weight loss, unaltered weight and weight gain groups) based on their weight change from baseline to follow-up. Ox-LDL was determined by baseline level of conjugated dienes in LDL lipids. Among the group of weight gainers, concentration of TAG reduced less (-0.14 vs. -0.33, p = 0.002), HDL-C reduced more (-0.31 vs. -0.16, p = 0.003) and ox-LDL/HDL-C ratio increased (3.0 vs. -0.2, p = 0.003) when compared to group of weight loss. Both T-C and LDL-C elevated more (0.14 vs. -0.21, p = 0.008; 0.31 vs. 0.07, p = 0.015) and TAG and ox-LDL reduced less (-0.33 vs. 0.20, p = 0.033; -3.33 vs. -0.68, p = 0.026) in unaltered weight group compared to weight loss group. The women who gained weight developed higher TAG and ox-LDL/HDL-C ratio as compared to those who lost weight. Postpartum weight retention of 3.4 kg or more is associated with atherogenic lipid profile.

The associations of oxidized high-density lipoprotein lipids with risk factors for atherosclerosis: the Cardiovascular Risk in Young Finns Study.

Scavenging and reverse transport of atherogenic oxidized lipids by high-density lipoprotein (HDL) was recently suggested to contribute to atheroprotection. We investigated the associations of oxidized HDL lipids (oxHDLlipids) with known risk factors for atherosclerosis in a population-based cross-sectional study of 1395 Finnish adults ages 24-39 years (54.9% women). Analysis of oxidized lipids in isolated HDL and LDL (oxLDLlipids) was based on the determination of conjugated dienes. Oxidized LDL was measured also with a method based on antibodies against oxidized Apo-B (oxLDLprot). Serum lipids and risk factors were measured. In multivariable models, oxHDLlipids were associated inversely with age (partial R(2)=2.9% in men, 0.8% in women) and directly with oxLDLlipids (partial R(2)=3.4% in men, 4.2% in women) after adjustment for Apo-A1 (partial R(2)=9.6% in men, 25.2% in women). In men, oxHDLlipids were also associated inversely with insulin (partial R(2)=1.1%). In women, oxHDLlipids were additionally inversely associated with waist circumference (partial R(2)=1.8%) and daily smoking (partial R(2)=0.7%) and directly with C-reactive protein (CRP; partial R(2)=0.5%) and alcohol use (partial R(2)=0.5%). We conclude that an elevated risk profile characterized primarily by advanced age is associated with lower oxHDLlipid levels in a population of young Finnish men and women. Higher levels of oxHDLlipids are additionally associated with higher oxLDLlipid levels. In men, higher insulin levels are also associated with lower oxHDLlipid levels. In women, increased waist circumference and daily smoking are also associated with lower oxHDLlipid levels, and higher CRP levels and alcohol use are associated with higher oxHDLlipid levels.

α-MSH analogue attenuates blood pressure elevation in DOCA-salt hypertensive mice.

Melanocyte-stimulating hormones, α-, ß- and γ-MSH, regulate important physiological functions including energy homeostasis, inflammation and sodium metabolism. Previous studies have shown that α-MSH increases sodium excretion and promotes vascular function in rodents, but it is unexplored whether these characteristics of α-MSH could translate into therapeutic benefits in the treatment of hypertension. Therefore, we first assessed the diuretic and natriuretic properties of the stable α-MSH analogue [Nle(4), D-Phe(7)]-α-MSH (NDP-α-MSH) and investigated whether it has protective effects in deoxycorticosterone acetate (DOCA)-salt hypertensive mice. Adult male C57Bl/6N mice were subjected to DOCA-salt treatment and randomized to receive intraperitoneal injections of either saline as vehicle or NDP-α-MSH (0.3 mg/kg/day for 14 days) starting 7 days after the DOCA-salt treatment. Systemic hemodynamics, serum and urine electrolytes, and oxidative stress markers were assessed in control sham-operated and DOCA-salt mice. NDP-α-MSH elicited marked diuretic and natriuretic responses that were reversible with the MC3/4 receptor antagonist SHU9119. Chronic NDP-α-MSH treatment attenuated blood pressure elevation in DOCA-salt mice without affecting the blood pressure of normotensive control animals. Owing to the enhanced sodium excretion, NDP-α-MSH-treated mice were protected from DOCA-salt-induced hypernatremia. DOCA-salt treatment mildly increased oxidative stress at the tissue level, but NDP-α-MSH had no significant effects on the oxidative stress markers. In conclusion, treatment with NDP-α-MSH increases urinary sodium excretion and protects against DOCA-salt-induced hypertension. These findings point to the potential future use of α-MSH analogues in the treatment of hypertension.

Young men with poor cardiorespiratory fitness combined with lower testosterone have high levels of oxidized LDL lipids--being fit alters this relationship.

PURPOSE: We hypothesized that lower androgen status together with poor physical fitness associates with atherogenic lipid profile and oxidative stress. METHODS: Volunteered young men (N = 846, mean age 25.1 ± 4.6 years) were categorized into unfit, average fit, and fit groups according to tertiles of maximal oxygen uptake, series of muscle endurance tests, and maximal upper and lower body strength. Furthermore, concentrations of serum testosterone (TT) and free testosterone (FT) were determined to divide participants into lower and higher testosterone (loTT, hiTT) and free testosterone (loFT, hiFT) subgroups, using medians as cut-off points. The participants were divided into subgroups according to Fitness × Testosterone (Unfit/Average Fit/ Fit × Low/High TT/FT), and the concentrations of serum lipids and ox-LDL were measured. RESULTS: The loTT/unfit cardiorespiratory subgroup had 29% higher concentration of ox-LDL compared with the loTT/fit cardiorespiratory subgroup (p = .044). The loTT / unfit cardiorespiratory subgroup had a significantly higher ratio of ox-LDL/HDL-cholesterol compared with the other five TT subgroups (p < .05, in all). While ox-LDL showed a gradual form of decrease from unfit to fit in loTT cardiorespiratory subgroups, no differences were seen in muscular fitness or maximal strength (upper and lower body) subgroups. CONCLUSIONS: Young men with poor cardiorespiratory fitness together with lower levels of TT have higher concentrations of ox-LDL. Good cardiorespiratory fitness combined with lower androgen levels is not related to atherogenic lipid profile. The combination of poor muscular fitness, or maximal muscle strength, and lower TT levels does not cause atherogenic lipid profile.

Elevated concentration of oxidized LDL together with poor cardiorespiratory and abdominal muscle fitness predicts metabolic syndrome in young men.

BACKGROUND: Metabolic syndrome (MetS) is associated with increased oxidized LDL (ox-LDL), systemic inflammation, and poor cardiorespiratory fitness. We examined affiliations of these factors and the effect of muscular fitness on MetS in young healthy men. METHODS: Physical fitness, ox-LDL, tumor necrosis factor α (TNFα), interleukin-6 (IL-6) and serum lipids were measured in a nationally representative sample of Finnish young men with and without MetS. Participants (mean age 25.1years) performed tests of maximal oxygen uptake (VO2max) and muscle fitness, and were divided into MetS (n=54, IDF 2007 criteria) and non-MetS (n=790). Age, smoking and leisure-time physical activity were used as covariates (ANCOVA). RESULTS: The MetS group had lower results in VO2max and all of the muscular fitness tests (excluding grip strength) (P<0.0001, in all). Ox-LDL, ox-LDL/HDL-cholesterol, ox-LDL/LDL-cholesterol, TNFα and IL-6 were all higher in the MetS group than in the non-MetS group (P<0.01, in all). In stepwise multivariate logistic regression analysis (adjusted to MetS criteria), higher ox-LDL (OR 1.118, 95% CI 1.078-1.160), lower VO2max (OR 0.938, 95% CI 0.901-0.977) and lower sit-ups (OR 0.898, 95% CI 0.844-0.956) predicted MetS (p<0.05, in all). CONCLUSIONS: Young men with MetS possess significantly poorer cardiorespiratory and muscle fitness, together with elevated systemic levels of ox-LDL, TNFα and IL-6 compared to non-MetS young men. Of these variables, ox-LDL, VO2max and sit-ups predicted MetS. Based on these findings, poor physical fitness and elevated concentration of ox-LDL are significant predisposing factors in the development of MetS.