Tadeusz Malinski

Ohio University, Афины, Ohio, United States

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Publications (210)1054.29 Total impact

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    ABSTRACT: The pathogenesis of the abdominal aortic aneurysm (AAA) shows several hallmarks of atherosclerotic and atherothrombotic disease, but comprises an additional, predominant feature of proteolysis resulting in the degradation and destabilization of the aortic wall. This review aims to summarize the current knowledge on AAA development, involving the accumulation of neutrophils in the intraluminal thrombus and their central role in creating an oxidative and proteolytic environment. Particular focus is placed on the controversial role of heme oxygenase 1/carbon monoxide and nitric oxide synthase/peroxynitrite which may exert both protective and damaging effects in the development of the aneurysm. Treatment indications as well as surgical and pharmacological options for AAA therapy are discussed in light of recent reports.
    05/2015; 2. DOI:10.3389/fcvm.2015.00019
  • Richard Preston Mason · Robert Jacob · J. Jose Corbalan · Tadeusz Malinski ·

    Journal of the American College of Cardiology 03/2015; 65(10):A2139. DOI:10.1016/S0735-1097(15)62139-8 · 16.50 Impact Factor
  • R P Mason · J J Corbalan · R F Jacob · H Dawoud · T Malinski ·
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    ABSTRACT: 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.
    Journal of physiology and pharmacology: an official journal of the Polish Physiological Society 02/2015; 66(1):65-72. · 2.39 Impact Factor
  • Tadeusz Malinski ·
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    ABSTRACT: The cytotoxic peroxynitrite (ONOO(-)) is an oxidation product of the cytoprotective nitric oxide (NO). Our studies support the hypothesis that the concentration ratio of NO and ONOO(-), [NO]/[ONOO(-)] can be a marker of nitroxidative imbalance, which subsequently correlates well with endothelial dysfunction and dysfunction of the cardiovascular system. Nanosensors, described here, have been used for simultaneous monitoring and measurement of NO and ONOO(-) release from a single endothelial cell. These nanosensors, with a diameter of 200-300 nm, can be positioned accurately in close proximity of 5-10 μm from the endothelial cell membrane. The response time of the sensors is better than a millisecond and the detection limit is 10(-9) M, with a linear concentration response of up to about 2 μM. The application of these sensors for the measurement of the balance and imbalance of [NO]/[ONOO(-)] in normal and dysfunctional endothelium is demonstrated.
    Methods in Molecular Biology 01/2015; 1208:139-55. DOI:10.1007/978-1-4939-1441-8_11 · 1.29 Impact Factor
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    ABSTRACT: Background: There are conflicting reports concerning the role of nitric oxide (NO) and oxidative stress in brain ischemic damage. In the present study, a nanomedical approach was utilized to elucidate the role of NO and peroxynitrite (ONOO-) imbalance in ischemic stroke. Methods: Nanosensors (diameter ~ 200 nm, detection limit of 10-9 molL-1, response time ~10 μs) were used to monitor in situ the concentration of NO and ONOO- . Adult male Sprague Dawley rats were given permanent middle cerebral artery occlusion (pMCAO) for 3 h, 12 h or 24 h. [NO]/[ONOO-] was measured in striatum, along with, constitutive nitric oxide synthase (cNOS) enzymes and heme oxygenase-1 (HO-1) expression and infarct volume. The [NO]/[ONOO-] was also monitored in pre-treated animals with simvastatin and atorvastatin in the presence of the cNOS inhibitor L-NAME. The effect of modulators of cNOS or NADPH oxidase (sepiapterin, PEG-SOD, VAS2870 and IN-7) on the [NO]/[ONOO-] was elucidated. Results: After 3 h of ischemia, NO decreased from 400 ± 20 nmolL-1 to 217 ± 11 nmolL-1 and ONOO- increased from 150 ± 9 nmolL-1 to 244 ± 9 nmolL-1.The [NO]/[ONOO-] balance shifted from 2.67 ± 0.06 to 0.89 ± 0.07 after 3 h of ischemia, indicating severe uncoupling of cNOS. The [NO]/[ONOO-] imbalance shifted with time of ischemia and correlated directly with the increase in infarct volume and expression of cNOS and HO-1. Treatment with simvastatin or atorvastatin partially, but significantly, restored [NO]/[ONOO-] balance and decreased infarct size in ischemic brain. Also, modulators of cNOS an NADPH oxidase restored [NO]/[ONOO-]. Conclusions: The imbalance between cytoprotective NO and cytotoxic ONOO- directly correlates with brain damage in ischemic stroke. The [NO]/[ONOO-] imbalance reflects on the level of uncoupled cNOS and the nitroxidative stress. [NO]/[ONOO-] imbalance increases cNOS and HO-1, which contributes to or prevents further brain damage, respectively. Balancing [NO]/[ONOO-] is the determinant in preventing or mollifying brain damage. Simvastatin or atorvastatin shifts favorably [NO]/[ONOO-], and may provide prophylactic treatment strategy for ischemic stroke.
    Journal of Nanomedicine & Nanotechnology 07/2014; 5(4):215. DOI:10.4172/2157-7439.1000215 · 5.72 Impact Factor
  • R. Preston Mason · Robert F. Jacob · J. Jose Corbalan · Tadeusz Malinski ·

    Journal of Clinical Lipidology 05/2014; 8(3):342-343. DOI:10.1016/j.jacl.2014.02.074 · 3.90 Impact Factor
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    ABSTRACT: Background: Previously, nitric oxide has been shown to possess antimicrobial effects. In this study, we aim to test the effect of glyceryl trinitrate (GTN) on Staphylococcus aureus growth during simulated extracorporeal circulation (SECC) and also to examine the effect of S. aureus, alone and in combination with GTN, on activation markers of the innate immune system during SECC. Methods: In an in vitro system of SECC, we measured GTN-induced changes in markers of leukocyte activation in whole blood caused by S. aureus infestation, as well as the effect of GTN on S. aureus growth. Results: GTN had no effect on S. aureus growth after 240 minutes SECC. Staphylococcus aureus reduced the expression of granulocyte Fcγ-receptor CD32 but stimulated the expression of monocyte CD32. Staphylococcus aureus stimulated expression of some leukocyte adhesion key proteins, activation marker CD66b, lipopolysaccharide-receptor CD14, and C3b-receptor CD35. Staphylococcus aureus and GTN addition induced significant increases in monocyte CD63 (lysosomal granule protein) levels. Conclusion: GTN does not affect S. aureus growth during SECC and has no effect on SECC-induced leukocyte activation.
    The Thoracic and Cardiovascular Surgeon 12/2013; 62(5). DOI:10.1055/s-0033-1363296 · 0.98 Impact Factor
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    ABSTRACT: Clinical trials have shown that amlodipine reduces cardiovascular events at a rate that is not predicted by changes in brachial arterial pressure alone. These findings may be explained, in part, by the pleiotropic effects of amlodipine on endothelial cell (EC) function. In this study, we elucidated the effect of amlodipine on nitric oxide (NO) bioavailability and cytotoxic peroxynitrite (ONOO(-)) and blood pressure (BP). Spontaneously hypertensive rats (SHRs) were treated with vehicle or amlodipine (5mg/kg/day) for 8 weeks and compared with untreated, baseline rats. NO and ONOO(-) release from aortic and glomerular ECs were measured ex vivo using amperometric nanosensors following maximal stimulation with calcium ionophore. BP was measured using the tail-cuff method. As compared with baseline, vehicle treatment had reduced aortic endothelial NO release from 157±11nM to 55±6nM and increased ONOO(-) from 69±7nM to 156±19nM. The NO/ONOO(-) ratio, a comprehensive measurement of eNOS function, decreased from 2.3±0.3 to 0.3±0.1. Compared with vehicle, amlodipine treatment restored NO to 101±3nM, decreased ONOO(-) to 50±4nM, and increased the NO/ONOO(-) ratio to 2.0±0.2, a level similar to baseline. Similar changes were observed for glomerular ECs. Mean arterial blood pressure increased from 149±3mm Hg (baseline) to 174±1mm Hg (vehicle). Amlodipine slightly, but significantly, decreased mean arterial blood pressure to 167±3mm Hg vs. vehicle treatment. Amlodipine increased NO bioavailability and decreased nitroxidative stress in SHRs with EC dysfunction disproportionately to BP changes. These direct, vascular effects of amlodipine on EC function may contribute to reduced risk for atherothrombotic events as observed in clinical trials.
    American Journal of Hypertension 10/2013; 27(3). DOI:10.1093/ajh/hpt202 · 2.85 Impact Factor
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    ABSTRACT: Nebivolol is a third-generation beta-blocker used to treat hypertension. The vasodilation properties of nebivolol have been attributed to nitric oxide (NO) release. However, the kinetics and mechanism of nebivolol-stimulated bioavailable NO are not fully understood. Using amperometric NO and peroxynitrite (ONOO-) nanosensors, beta3-receptor (agonist: L-755,507; antagonists: SR59230A and L-748,337), ATP efflux (the mechanosensitive ATP channel blocker, gadolinium) and P2Y-receptor (agonists: ATP and 2-MeSATP; antagonist: suramin) modulators, superoxide dismutase and a NADPH oxidase inhibitor (VAS2870), we evaluated the kinetics and balance of NO and ONOO- stimulated by nebivolol in human umbilical vein endothelial cells (HUVECs). NO and ONOO- were measured with nanosensors (diameter ~ 300 nm) placed 5 +/- 2 mum from the cell membrane and ATP levels were determined with a bioluminescent method. The kinetics and balance of nebivolol-stimulated NO and ONOO- were compared with those of ATP, 2-MeSATP, and L-755,507. Nebivolol stimulates endothelial NO release through beta3-receptor and ATP-dependent, P2Y-receptor activation with relatively slow kinetics (75 +/- 5nM/s) as compared to the kinetics of ATP (194 +/- 10nM/s), L-755,507 (108 +/- 6nM/s), and 2-MeSATP (105 +/- 5nM/s). The balance between cytoprotective NO and cytotoxic ONOO- was expressed as the ratio of [NO]/[ONOO-] concentrations. This ratio for nebivolol was 1.80 +/- 0.10 and significantly higher than that for ATP (0.80 +/- 0.08), L-755,507 (1.08 +/- 0.08), and 2-MeSATP (1.09 +/- 0.09). Nebivolol induced ATP release in a concentration-dependent manner. The two major pathways (ATP efflux/P2Y receptors and beta3 receptors) and several steps of nebivolol-induced NO and ONOO- stimulation are mainly responsible for the slow kinetics of NO release and low ONOO-. The net effect of this slow kinetics of NO is reflected by a favorable high ratio of [NO]/[ONOO-] which may explain the beneficial effects of nebivolol in the treatment of endothelial dysfunction, hypertension, heart failure, and angiogenesis.
    BMC pharmacology & toxicology 09/2013; 14(1):48. DOI:10.1186/2050-6511-14-48
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    ABSTRACT: BACKGROUND: Reactive oxygen species are major determinants of vascular aging. JunD, a member of the activated protein-1 family of transcription factors, is emerging as a major gatekeeper against oxidative stress. However, its contribution to reactive oxygen species homeostasis in the vasculature remains unknown. METHODS AND RESULTS: Endothelium-dependent vasorelaxation was impaired in young and old JunD(-/-) mice (6 and 22 months old) compared with age-matched wild-type mice. JunD(-/-) mice displayed an age-independent decline in endothelial nitric oxide release and endothelial nitric oxide synthase activity and increased mitochondrial superoxide formation and peroxynitrite levels. Furthermore, vascular expression and activity of the free radical scavengers manganese and extracellular superoxide dismutase and aldehyde dehydrogenase 2 were reduced, whereas the NADPH oxidase subunits p47phox, Nox2, and Nox4 were upregulated. These redox changes were associated with premature vascular aging, as shown by reduced telomerase activity, increased β-galactosidase-positive cells, upregulation of the senescence markers p16(INK4a) and p53, and mitochondrial disruption. Interestingly, old wild-type mice showed a reduction in JunD expression and transcriptional activity resulting from promoter hypermethylation and binding with tumor suppressor menin, respectively. In contrast, JunD overexpression blunted age-induced endothelial dysfunction. In human endothelial cells, JunD knockdown exerted a similar impairment of the O2(-)/nitric oxide balance that was prevented by concomitant NADPH inhibition. In parallel, JunD expression was reduced in monocytes from old versus young healthy subjects and correlated with mRNA levels of scavenging and oxidant enzymes. CONCLUSIONS: JunD provides protection in aging-induced endothelial dysfunction and may represent a novel target to prevent reactive oxygen species-driven vascular aging.
    Circulation 02/2013; 127(11). DOI:10.1161/CIRCULATIONAHA.112.000826 · 14.43 Impact Factor
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    ABSTRACT: 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 sICAM-1 levels in hypertensive rats. Spontaneously hypertensive (SH) rats were treated with vehicle or saxagliptin (10 mg/kg/day) 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 to vehicle. Saxagliptin also reduced mean arterial pressure from 170 ± 10 to 158 ± 10 mmHg (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.
    Journal of cardiovascular pharmacology 08/2012; 60(5). DOI:10.1097/FJC.0b013e31826be204 · 2.14 Impact Factor
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    Journal of the American College of Cardiology 03/2012; 59(13). DOI:10.1016/S0735-1097(12)61544-7 · 16.50 Impact Factor
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    ABSTRACT: Amorphous silica nanoparticles (SiNP) can be used in medical technologies and other industries leading to human exposure. However, an increased number of studies indicate that this exposure may result in cardiovascular inflammation and damage. A high ratio of nitric oxide to peroxynitrite concentrations ([NO]/[ONOO(-)]) is crucial for cardiovascular homeostasis and platelet hemostasis. Therefore, we studied the influence of SiNP on the platelet [NO]/[ONOO(-)] balance and platelet aggregation. Nanoparticle-platelet interaction was examined using transmission electron microscopy. Electrochemical nanosensors were used to measure the levels of NO and ONOO(-) released by platelets upon nanoparticle stimulation. Platelet aggregation was studied using light aggregometry, flow cytometry, and phase contrast microscopy. Amorphous SiNP induced NO release from platelets followed by a massive stimulation of ONOO(-) leading to an unfavorably low [NO]/[ONOO(-)] ratio. In addition, SiNP induced an upregulation of selectin P expression and glycoprotein IIb/IIIa activation on the platelet surface membrane, and led to platelet aggregation via adenosine diphosphate and matrix metalloproteinase 2-dependent mechanisms. Importantly, all the effects on platelet aggregation were inversely proportional to nanoparticle size. The exposure of platelets to amorphous SiNP induces a critically low [NO]/[ONOO(-)] ratio leading to platelet aggregation. These findings provide new insights into the pharmacological profile of SiNP in platelets.
    International Journal of Nanomedicine 02/2012; 7:631-9. DOI:10.2147/IJN.S28293 · 4.38 Impact Factor
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    ABSTRACT: AIM Angiotensin II receptor blockers (ARBs) improve endothelial cell (EC)-dependent vasodilation in patients with hypertension through suppression of angiotensin II type 1 receptors but may have additional and differential effects on endothelial nitric oxide (NO) synthase (eNOS) function. To investigate this question, we tested the effects of various ARBs on NO release in ECs from multiple donors, including those with eNOS genetic variants linked to higher cardiovascular risk. METHODS The effects of ARBs (losartan, olmesartan, telmisartan, valsartan), at 1 mu m, on NO release were measured with nanosensors in human umbilical vein ECs obtained from 18 donors. NO release was stimulated with calcium ionophore (1 mu m) and its maximal concentration was correlated with eNOS variants. The eNOS variants were determined by a single nucleotide polymorphism in the promoter region (T-786C) and in the exon 7 (G894T), linked to changes in NO metabolism. RESULTS All of the ARBs caused an increase in NO release as compared with untreated samples (P < 0.01, n= 45 in all eNOS variants). However, maximal NO production was differentially influenced by eNOS genotype. Olmesartan increased maximal NO release by 30%, which was significantly greater (P < 0.01, n= 45 in all eNOS variants) than increases observed with other ARBs. CONCLUSIONS The ARBs differentially enhanced NO release in ECs in a manner influenced by eNOS single nucleotide polymorphisms. These findings provide new insights into the effects of ARBs on EC-dependent vasodilation and eNOS function.
    British Journal of Clinical Pharmacology 01/2012; 74(1):141-6. DOI:10.1111/j.1365-2125.2012.04189.x · 3.88 Impact Factor
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    J Jose Corbalan · Carlos Medina · Adam Jacoby · Tadeusz Malinski · Marek W Radomski ·
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    ABSTRACT: The purpose of this study was to investigate the mechanism of noxious effects of amorphous silica nanoparticles on human endothelial cells. Nanoparticle uptake was examined by transmission electron microscopy. Electrochemical nanosensors were used to measure the nitric oxide (NO) and peroxynitrite (ONOO(-)) released by a single cell upon nanoparticle stimulation. The downstream inflammatory effects were measured by an enzyme-linked immunosorbent assay, real-time quantitative polymerase chain reaction, and flow cytometry, and cytotoxicity was measured by lactate dehydrogenase assay. We found that the silica nanoparticles penetrated the plasma membrane and rapidly stimulated release of cytoprotective NO and, to a greater extent, production of cytotoxic ONOO(-). The low [NO]/[ONOO(-)] ratio indicated increased nitroxidative/oxidative stress and correlated closely with endothelial inflammation and necrosis. This imbalance was associated with nuclear factor κB activation, upregulation of key inflammatory factors, and cell death. These effects were observed in a nanoparticle size-dependent and concentration-dependent manner. The [NO]/[ONOO(-)] imbalance induced by amorphous silica nanoparticles indicates a potentially deleterious effect of silica nanoparticles on vascular endothelium.
    International Journal of Nanomedicine 11/2011; 6:2821-35. DOI:10.2147/IJN.S25071 · 4.38 Impact Factor
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    ABSTRACT: Generation of reactive oxygen species (ROS) is a key feature of vascular disease. Activation of the nuclear enzyme poly (adenosine diphosphate [ADP]-ribose) polymerase-1 (PARP-1) is a downstream effector of oxidative stress. PARP-1(-/-) and PARP-1(+/+) mice were injected with paraquat (PQ; 10 mg/kg i.p.) to induce intracellular oxidative stress. Aortic rings were suspended in organ chambers for isometric tension recording to analyze vascular function. PQ treatment markedly impaired endothelium-dependent relaxations to acetylcholine in PARP-1(-/-), but not PARP-1(+/+) mice (p<0.0001). Maximal relaxation was 45% in PQ treated PARP-1(-/-) mice compared to 79% in PARP-1(+/+) mice. In contrast, endothelium-independent relaxations to sodium nitroprusside (SNP) were not altered. After PQ treatment, l-NAME enhanced contractions to norepinephrine by 2.0-fold in PARP-1(-/-) mice, and those to acetylcholine by 3.3-fold, respectively, as compared to PARP-1(+/+) mice. PEG-superoxide dismutase (SOD) and PEG-catalase prevented the effect of PQ on endothelium-dependent relaxations to acetylcholine in PARP-1(-/-) mice (p<0.001 vs. PQ treated PARP-1(+/+) mice. Indomethacin restored endothelium-dependent relaxations to acetylcholine in PQ treated PARP-1(-/-) mice (p<0.05 vs. PQ treated PARP-1(+/+). PARP-1 protects from acute intracellular oxidative stress induced endothelial dysfunction by inhibiting ROS induced production of vasoconstrictor prostanoids.
    Biochemical and Biophysical Research Communications 11/2011; 414(4):641-6. DOI:10.1016/j.bbrc.2011.09.029 · 2.30 Impact Factor
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    ABSTRACT: Endothelial cell (EC) dysfunction contributes to insulin resistance in diabetes and is characterized by reduced nitric oxide (NO) release, increased nitroxidative stress and enhanced inflammation. The purpose of this study was to test the effect of improved postprandial glucose control on EC function in insulin-resistant rats as compared to fasting glucose (FG) changes. Obese Zucker rats were treated with 10 mg/kg/day saxagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor, for 4 or 8 weeks and compared to lean rats. NO and peroxynitrite (ONOO(-)) release from aortic and glomerular ECs was measured ex vivo using amperometric approaches and correlated with FG, postprandial glucose, insulin, soluble CD40 (sCD40) and L-citrulline levels. Saxagliptin treatment improved NO production and reduced ONOO(-) release prior to any observed changes in FG levels. In untreated obese animals, NO release from aortic and glomerular ECs decreased by 22% and 31%, respectively, while ONOO(-) release increased by 26% and 40%. Saxagliptin increased aortic and glomerular NO release by 18% and 31%, respectively, with comparable reductions in ONOO(-) levels; the NO/ONOO(-) ratio, an indicator of NO synthase coupling, increased by >40%. Improved glycemic control was further associated with a reduction in sCD40 levels by more than ten-fold (from 300 ± 206 to 22 ± 22 pg/mL, p < 0.001). These findings indicate that enhanced glycemic control with DPP4 inhibition improved NO release and reduced inflammation in a manner not predicted by FG changes alone.
    Journal of atherosclerosis and thrombosis 06/2011; 18(9):774-83. DOI:10.5551/jat.7666 · 2.73 Impact Factor
  • Preston Mason · Robert F. Jacob · Ruslan Kubant · Adam M. Jacoby · Tadeusz Malinski ·

    Journal of the American College of Cardiology 04/2011; 57(14). DOI:10.1016/S0735-1097(11)61434-4 · 16.50 Impact Factor
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    Journal of the American College of Cardiology 04/2011; 57(14). DOI:10.1016/S0735-1097(11)61431-9 · 16.50 Impact Factor
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    ABSTRACT: Cardiovascular disease remains the leading cause of morbidity and premature mortality in most industrialized countries as well as in developing nations. A pro-oxidative state appears to promote and/or exacerbate vascular disease complications. Furthermore, a state of low-grade chronic inflammation can promote increased oxidative stress and lead to endothelial cell and platelet dysfunction ultimately contributing to thrombogenesis. In this study, the effect of a proprietary astaxanthin prodrug (CDX-085) on thrombus formation was investigated using a mouse model of arterial thrombosis. The influence of free astaxanthin, the active drug of CDX-085, on human endothelial cells and rat platelets was evaluated to investigate potential mechanisms of action. Oral administration of CDX-085 (0.4% in chow, approximately 500 mg/kg/day) to 6-8 week old C57BL/6 male mice for 14 days resulted in significant levels of free astaxanthin in the plasma, liver, heart and platelets. When compared to control mice, the CDX-085 fed group exhibited significant increases in basal arterial blood flow and significant delays in occlusive thrombus formation following the onset of vascular endothelial injury. Primary human umbilical vein endothelial cells (HUVECs) and platelets isolated from Wistar-Kyoto rats treated with free astaxanthin demonstrated significantly increased levels of released nitric oxide (NO) and significantly decreased peroxynitrite (ONOO-) levels. Observations of increased NO and decreased ONOO- levels in endothelial cells and platelets support a potential mechanism of action for astaxanthin (CDX-085 active drug). These studies support the potential of CDX-085 and its metabolite astaxanthin in the treatment or prevention of thrombotic cardiovascular complications.
    Thrombosis Research 10/2010; 126(4):299-305. DOI:10.1016/j.thromres.2010.07.003 · 2.45 Impact Factor

Publication Stats

9k Citations
1,054.29 Total Impact Points


  • 2000-2015
    • Ohio University
      • Department of Chemistry and Biochemistry
      Афины, Ohio, United States
  • 2010
    • Molecular and Cellular Biology Program
      Seattle, Washington, United States
    • Harvard Medical School
      • Department of Medicine
      Boston, Massachusetts, United States
  • 1992-2010
    • University of Idaho
      • Department of Chemistry
      Moscow, Idaho, United States
  • 1984-2009
    • Oakland University
      • Department of Chemistry
      Rochester, MI, United States
  • 2008
    • Brigham and Women's Hospital
      Boston, Massachusetts, United States
    • Alice Ho Miu Ling Nethersole Hospital
      Ch’üan-wan, Tsuen Wan, Hong Kong
  • 2006
    • Yale University
      • Department of Electrical Engineering
      New Haven, Connecticut, United States
  • 2005
    • Harvard University
      Cambridge, Massachusetts, United States
    • University of Alberta
      • Department of Pharmacology
      Edmonton, Alberta, Canada
    • University of Texas Health Science Center at Houston
      Houston, Texas, United States
  • 2002
    • University of Vienna
      • Department of Surgery
      Wien, Vienna, Austria
  • 2001
    • Medical University of Gdansk
      • Department of Clinical Chemistry
      Danzig, Pomeranian Voivodeship, Poland
  • 1998
    • University Hospital Zürich
      Zürich, Zurich, Switzerland
  • 1997
    • University of North Carolina at Chapel Hill
      • Department of Medicine
      North Carolina, United States
  • 1995
    • University of Pennsylvania
      • Department of Oral Medicine
      Filadelfia, Pennsylvania, United States
  • 1994
    • William Beaumont Army Medical Center
      El Paso, Texas, United States
  • 1982-1984
    • University of Houston
      • Department of Chemistry
      Houston, Texas, United States
  • 1979-1981
    • Poznan University of Technology
      Posen, Greater Poland Voivodeship, Poland