Oxidized dietary lipids induce vascular inflammation and atherogenesis in post-menopausal rats: estradiol and selected antihyperlipidemic drugs restore vascular health in vivo.

BACKGROUND: Thermoxidation of edible oil through deep fat frying results in the generation of several oxidized products that promote lipid peroxidation and ROS production when eaten. Consumption of thermoxidized oil in post-menopausal conditions where the estrogen level is low contributes to cardiovascular disease. This study evaluates the role of estradiol and antihyperlipidemic agents (AHD) in restoring the vascular health of ovariectomized (OVX) rats fed with thermoxidized palm oil (TPO) and thermoxidized soya oil (TSO) diets. METHOD: A total of 10 groups of rats (n = 6) were set up for the experiment. Group I (normal control) rats were sham handled while other groups were OVX to bring about estrogen deficient post-menopausal state. Group II (OVX only) was not treated and received normal rat chow. Groups III-X were fed with either TPO or TSO diet for 12 weeks and treated with estradiol (ETD) 0.2 mg/kg/day, atorvastatin (ATV) 10 mg/kg/day, and a fixed-dose combination of ezetimibe and ATV (EZE 3 mg/kg/day + ATV 10 mg/kg/day). RESULTS: Pro-atherogenic lipids levels were significantly elevated in untreated TSO and TPO groups compared to OVX and sham, resulting in increased atherogenic and Coronary-risk indices. Treatment with Estradiol and AHDs significantly reduced the total cholesterol, triglycerides, low-density lipoprotein cholesterol as well as AI and CRI compared to untreated TSO and TPO groups, whereas TSO and TPO groups showed significant elevation in these parameters compared to Group I values. Moreover, aortic TNF-α levels were extremely elevated in the untreated TSO and TPO compared to Group I. TNF-α levels were significantly reduced in rats treated with AHDs and ETD. Localized oxidative stress was indicated in the aortic tissues of TSO and TPO-fed OVX rats by increased malondialdehyde and decreased glutathione, catalase, and superoxide dismutase levels. This contributed to a depletion in aortic nitric oxide. AHDs and ETD replenished the nitric oxide levels significantly. Histological evaluation of the aorta of TSO and TPO rats revealed increased peri-adventitia fat, aortic medial hypertrophy, and aortic recanalization. These pathologic changes were less seen in AHDs and ETD rats. CONCLUSION: This study suggests that ETD and AHDs profoundly attenuate oxidized lipid-induced vascular inflammation and atherogenesis through oxidative-stress reduction and inhibition of TNF-α signaling.

Novel Niacin Receptor Agonists: A Promising Strategy for the Treatment of Dyslipidemia.

BACKGROUND: Hyperlipidemia is characterized by high level of cholesterol and triglycerides in blood. Various classes of drugs like statins, fibrates, niacin etc. are used for treatment of hyperlipidaemia. OBJECTIVE: Niacin, which is one of the beneficial anti-hyperlipidemic agents, helps decreasing LDL cholesterol by 20 to 40% and causes increase of HDL cholesterol by 20 to 35%. However cutaneous flushing, loss of glucose tolerance, liver toxicity are the reported side effects of niacin therapy responsible for decreased patient compliance. Very recently, the G protein coupled receptor (GPCR); GPR109A located on the adipocytes has been identified as the receptor for activation of niacin. METHOD: In-vitro studies have demonstrated that GPR109A receptor having high affinity for niacin. The present review attempts to provide a systematic presentation of the various chemical classes of compounds that have been reported as novel niacin receptor agonists including pyrazole-3-carboxylic acids, urea derivatives, anthranilic acids, biaryl anthranilides, tetrahydro anthranilic acid, xanthines, barbituric acid, bicyclic pyrazole carboxylic acids, pyrido pyrimidinones, pyrazolyl propionyl cyclohexenamides, pyrazole acids etc. Results: As the design of GPR109A receptor agonists offers a promising solution for treatment of dyslipidemia, this review will be beneficial for medicinal and drug discovery chemists to expediate the process of discovery of new class of anti-hyperlipidemic agent with favorable lipid lowering profile with increase in HDL levels. CONCLUSION: This review explains novel GPR109A receptor agonists for the treatment of dyslipidemia.