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Beverly Cove, MA, United States

Mason R.P.,Harvard University | Mason R.P.,Elucida Research LLC | Jacob R.F.,Harvard University | Kubant R.,Ohio University | And 3 more authors.
Journal of Cardiovascular Pharmacology | Year: 2012

Most patients with diabetes also have hypertension, a risk factor associated with atherothrombotic disease and characterized by endothelial cell (EC) dysfunction and loss of nitric oxide (NO) bioavailability. Recent studies suggest a possible antihypertensive effect with dipeptidyl peptidase-4 (DPP4) inhibition; however, the underlying mechanism is not understood. In this study, we tested the effects of the DPP4 inhibitor, saxagliptin, on EC function, blood pressure, and soluble intercellular adhesion molecule 1 (sICAM-1) levels in hypertensive rats. Spontaneously hypertensive rats were treated with vehicle or saxagliptin (10 mg•-1kg•day-1) for 8 weeks. NO and peroxynitrite (ONOO) release from aortic and glomerular ECs was stimulated with calcium ionophore and measured using electrochemical nanosensor technology. Changes in EC function were correlated with fasting glucose levels. Saxagliptin treatment was observed to increase aortic and glomerular NO release by 22% (P < 0.001) and 23% (P < 0.001), respectively, with comparable reductions in ONOO levels; the NO/ONOO ratio increased by >50% in both EC types (P < 0.001) as compared with vehicle. Saxagliptin also reduced mean arterial pressure from 170 ± 10 to 158 ± 10 mm Hg (P < 0.001) and decreased sICAM-1 levels by 37% (P < 0.01). The results of this study suggest that DPP4 inhibition reduces blood pressure and inflammation in hypertensive rats while increasing NO bioavailability. Copyright © 2012 by Lippincott Williams & Wilkins. Source

Mizuno Y.,Bunkyo University | Jacob R.F.,Elucida Research LLC | Mason R.P.,Brigham and Womens Hospital
Therapy | Year: 2011

Reduced cardiovascular events and mortality have been reported for hypertensive subjects treated with dihydropyridine-type calcium channel blockers (CCBs) and inhibitors of the renin-â€"angiotensin system (RAS) in clinical trials. Recent evidence suggests that these agents may have vascular benefits that cannot be attributed to the reduction of blood pressure alone. Dihydropyridine-type CCBs and RAS blockers have been shown to improve endothelial activity while reducing inflammation. These changes in vascular activity have been confirmed by pulse wave analyses, which show a reduced impact of pressure wave reflections on central systolic blood pressure. In this article, we examine the separate and combined effects of CCB and RAS inhibition in reducing cardiovascular risk through enhanced vascular function. © 2011 Future Medicine Ltd. Source

Mason R.P.,Harvard University | Mason R.P.,Elucida Research LLC | Sherratt S.C.R.,Elucida Research LLC | Jacob R.F.,Elucida Research LLC
Journal of Cardiovascular Pharmacology | Year: 2016

Eicosapentaenoic acid (EPA) is a triglyceride-lowering agent that reduces circulating levels of the apolipoprotein B (apoB)-containing lipoprotein particles small dense low-density lipoprotein (sdLDL), very-low-density lipoprotein (VLDL), and oxidized low-density lipoprotein (LDL). These benefits may result from the direct antioxidant effects of EPA. To investigate this potential mechanism, these particles were isolated from human plasma, preincubated with EPA in the absence or presence of atorvastatin (active) metabolite, and subjected to copper-initiated oxidation. Lipid oxidation was measured as a function of thiobarbituric acid reactive substances formation. EPA inhibited sdLDL (IC50 ~2.0 μM) and LDL oxidation (IC50 ~2.5 μM) in a dose-dependent manner. Greater antioxidant potency was observed for EPA in VLDL. EPA inhibition was enhanced when combined with atorvastatin metabolite at low equimolar concentrations. Other triglyceride-lowering agents (fenofibrate, niacin, and gemfibrozil) and vitamin E did not significantly affect sdLDL, LDL, or VLDL oxidation compared with vehicle-treated controls. Docosahexaenoic acid was also found to inhibit oxidation in these particles but over a shorter time period than EPA. These data support recent clinical findings and suggest that EPA has direct antioxidant benefits in various apoB-containing subfractions that are more pronounced than those of other triglyceride-lowering agents and docosahexaenoic acid. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved. Source

Mason R.P.,Harvard University | Mason R.P.,Elucida Research LLC | Jacob R.F.,Elucida Research LLC
Biochimica et Biophysica Acta - Biomembranes | Year: 2015

Lipid oxidation leads to endothelial dysfunction, inflammation, and foam cell formation during atherogenesis. Glucose also contributes to lipid oxidation and promotes pathologic changes in membrane structural organization, including the development of cholesterol crystalline domains. In this study, we tested the comparative effects of eicosapentaenoic acid (EPA), an omega-3 fatty acid indicated for the treatment of very high triglyceride (TG) levels, and other TG-lowering agents (fenofibrate, niacin, and gemfibrozil) on lipid oxidation in human low-density lipoprotein (LDL) as well as membrane lipid vesicles prepared in the presence of glucose (200 mg/dL). We also examined the antioxidant effects of EPA in combination with atorvastatin o-hydroxy (active) metabolite (ATM). Glucose-induced changes in membrane structural organization were measured using small angle x-ray scattering approaches and correlated with changes in lipid hydroperoxide (LOOH) levels. EPA was found to inhibit LDL oxidation in a dose-dependent manner (1.0-10.0 μM) and was distinguished from the other TG-lowering agents, which had no significant effect as compared to vehicle treatment alone. Similar effects were observed in membrane lipid vesicles exposed to hyperglycemic conditions. The antioxidant activity of EPA, as observed in glucose-treated vesicles, was significantly enhanced in combination with ATM. Glucose treatment produced highly-ordered, membrane-restricted, cholesterol crystalline domains, which correlated with increased LOOH levels. Of the agents tested in this study, only EPA inhibited glucose-induced cholesterol domain formation. These data demonstrate that EPA, at pharmacologic levels, inhibits hyperglycemia-induced changes in membrane lipid structural organization through a potent antioxidant mechanism associated with its distinct, physicochemical interactions with the membrane bilayer. Source

Mason R.P.,Harvard University | Mason R.P.,Elucida Research LLC | Corbalan J.J.,Ohio University | Jacob R.F.,Elucida Research LLC | And 2 more authors.
Journal of Physiology and Pharmacology | Year: 2015

Clinical trials have shown that atorvastatin benefits patients with diabetes even with normal baseline LDL levels. We hypothesized that atorvastatin improves endothelial cell (EC) function and reduces inflammation in hypertensive rats with diabetes. Non-diabetic and streptozotocin-induced type 2 diabetic male spontaneously hypertensive rats (SHR) were treated with atorvastatin at 20 mg/kg/day. After five weeks, nitric oxide (NO) and peroxynitrite (ONOO-) were measured in aortic and glomerular endothelial cells. A tandem of nanosensors was used to simultaneously measure NO and ONOO- concentration and their ratio [NO]/[ONOO-] was monitored with a time resolution better than 10 μs and detection limit 1 nM. [NO]/[ONOO-] was applied as a marker of endothelial NO synthase (eNOS) uncoupling, endothelial dysfunction and nitroxidative stress. Glucose, cholesterol, blood pressure (BP), and the cytokine RANTES were also measured. Diabetic SHR rats had elevated glucose (355 ± 38 mg/dL), mean BP (172 ± 15 mmHg), and plasma RANTES (38.4 ± 2.7 ng/mL), low endothelial NO bioavailability and high ONOO–. Maximal NO release measured 267 ± 29 nM in aortic endothelium of SHR rats and 214 ± 20 nM for diabetic SHR rats; [NO]/[ONOO-] was 0.88 ± 12 and 0.61 ± 0.08, respectively. [NO]/[ONOO-] ratios below one indicate a high uncoupling of eNOS, endothelial dysfunction and high nitroxidative stress. Atorvastatin treatment partially restored endothelial function by increasing NO level by 98%, reducing ONOO- by 40% and favorably elevating [NO]/[ONOO-] to 1.1 ± 0.2 for diabetic SHR rats and 1.6 ± 0.3 for SHR rats. The effects of atorvastatin were similar in glomerular endothelial cells and were partially reproduced by modulators of eNOS or NADPH oxidase. Atorvastatin had no significant effect on fasting glucose or total cholesterol levels but reduced mean BP by 21% and 11% in diabetic and non-diabetic animals, respectively. Atorvastatin also reduced RANTES levels by 50%. Atorvastatin favorably increased the [NO]/[ONOO-] balance, enhanced endothelial cytoprotective NO, decreased cytotoxic ONOO- and reduced BP, inflammation and RANTES levels in diabetic, hypertensive rats without altering cholesterol levels. These findings provide insights into mechanisms of restoration of endothelial function and vascular protection by atorvastatin in diabetes and hypertension. © 2015, Polish Physiological Society. All rights reserved. Source

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