Inhibition of Pro-Inflammatory Cytokine Secretion by Select Antioxidants in Human Coronary Artery Endothelial Cells.

Inflammatory and oxidative stress in endothelial cells are implicated in the pathogenesis of premature atherosclerosis in diabetes. To determine whether high-dextrose concentrations induce the expression of pro-inflammatory cytokines, human coronary artery endothelial cells (HCAEC) were exposed to either 5.5 or 27.5 mM dextrose for 24-hours and interleukin-1ß (IL-1ß), interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor α (TNF α) levels were measured by enzyme immunoassays. To determine the effect of antioxidants on inflammatory cytokine secretion, cells were also treated with α-tocopherol, ascorbic acid, and the glutathione peroxidase mimetic ebselen. Only the concentration of IL-1ß in culture media from cells exposed to 27.5 mM dextrose increased relative to cells maintained in 5.5 mM dextrose. Treatment with α-tocopherol (10, 100, and 1,000 µM) and ascorbic acid (15, 150, and 1,500 µM) at the same time that the dextrose was added reduced IL-1ß, IL-6, and IL-8 levels in culture media from cells maintained at 5.5 mM dextrose but had no effect on IL-1ß, IL-6, and IL-8 levels in cells exposed to 27.5 mM dextrose. However, ebselen treatment reduced IL-1ß, IL-6, and IL-8 levels in cells maintained in either 5.5 or 27.5 mM dextrose. IL-2 and TNF α concentrations in culture media were below the limit of detection under all experimental conditions studied suggesting that these cells may not synthesize detectable quantities of these cytokines. These results suggest that dextrose at certain concentrations may increase IL-1ß levels and that antioxidants have differential effects on suppressing the secretion of pro-inflammatory cytokines in HCAEC.

The Effects of Known Cardioprotective Drugs on Proinflammatory Cytokine Secretion From Human Coronary Artery Endothelial Cells.

BACKGROUND: Endothelial cell dysfunction in diabetes is involved in the pathogenesis and progression of premature atherosclerosis. High-dextrose has been shown to induce both oxidative stress and endoplasmic reticulum stress in cultured human coronary artery endothelial cells (HCAEC). STUDY QUESTION: To determine whether or not several classes of cardioprotective drugs inhibit proinflammatory cytokine expression by HCAEC. MEASURES AND OUTCOMES: To determine the effects of high dextrose on expression of proinflammatory cytokines by HCAEC, cells were treated with either 5.5 mM or 27.5 mM dextrose for 24 hours and interleukin-1ß (IL-1ß), interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor α were measured by enzyme immunoassay in the presence or absence of known cardioprotective drugs, including select ß-blockers, statins, and renin-angiotensin system inhibitors. RESULTS: IL-1ß levels increased significantly in cells treated with high dextrose; however, IL-6 and IL-8 levels did not change. Treatment of cells with carvedilol, atenolol, and propranolol decreased levels of all 3 cytokines in cells exposed to either 5.5 or 27.5 mM dextrose. Similar effects on IL-1ß, IL-6, and IL-8 levels were observed when cells were treated with simvastatin, pravastatin, and the renin-angiotensin system inhibitors spironolactone, captopril, lisinopril, candesartan, and losartan. No Il-2 or tumor necrosis factor α expression was observed in any of the experiments indicating that HCAEC do not express these cytokines. CONCLUSIONS: We conclude that each of the classes of drugs tested possess pleiotropic anti-inflammatory activities and are effective in both low- and high-dextrose-treated cells.

Effects of yoga on inflammation and exercise capacity in patients with chronic heart failure.

BACKGROUND: Despite recent advances in pharmacologic and device therapy, morbidity and mortality from heart failure (HF) remain high. Yoga combines physical and breathing exercises that may benefit patients with HF. We hypothesized that an 8-week regimen of yoga in addition to standard medical therapy would improve exercise capacity, inflammatory markers, and quality of life (QoL) in patients with HF. METHODS AND RESULTS: New York Heart Association Class I-III HF patients were randomized to yoga treatment (YT) or standard medical therapy (MT). Measurements included a graded exercise test (GXT) to V O(2Peak) and the following serum biomarkers: interleukin-6 (IL-6), high-sensitivity C-reactive protein (hsCRP), and extracellular superoxide dismutase (EC-SOD). The Minnesota Living with Heart Failure Questionnaire (MLHFQ) was administered to assess changes in QoL. A total of 19 patients were enrolled after the initial screening. Of the 19 patients, 9 were randomized to YT and 10 to MT. Patients had a mean EF of 25%. GXT time and V O(2Peak) were significantly improved in the YT versus MT groups (+18% in the YT and -7.5% in MT; P = .03 vs. control and +17 in YT and -7.1 in MT; P = .02, respectively). There were statistically significant reductions in serum levels of IL-6 and hsCRP and an increase in EC-SOD in the YT group (all P < .005 vs. MT). MLHFQ scores improved by 25.7% in the YT group and by 2.9% in the MT group. CONCLUSIONS: Yoga improved exercise tolerance and positively affected levels of inflammatory markers in patients with HF, and there was also a trend toward improvements in QoL.

Mechanisms of benefit of angiotensin receptor blockers in coronary atherosclerosis.

There is mounting evidence that dysfunction of the renin angiotensin system is a vital contributor to the development of atherosclerosis. Nonetheless, the efficacy of angiotensin receptor blockers on clinical outcomes in patients with coronary atherosclerosis has been limited. This review will examine the potential mechanisms by which angiotensin receptor blockers potentially affect several key steps in the atherosclerotic process: endothelial function, inflammation, and thrombosis. Despite the mounting evidence for these agents on multiple processes in the development of atherosclerosis, their clinical utility in patients with coronary artery disease remains unclear.

Regulation of apolipoprotein A-I gene expression by the histamine H1 receptor: Requirement for NF-κB.

AIMS: Earlier it had been found by us that apolipoprotein A-I (apo A-I) is suppressed by histamine in HepG2 cells. Histamine has been shown to regulate NF-κB activity, though not in hepatocytes. Therefore we examined the role of the histamine receptors and NF-κB in histamine-mediated apo A-I gene expression in HepG2 liver cells. MAIN METHODS: The effect of histamine on histamine H1 receptor expression, and NF-κB p65 and p50 subunits was examined by Western blot. Histamine H1 receptor involvement was examined by loss-of-function (via siRNA) and gain-of-function studies overexpressing the histamine H1 receptor. The requirement for the p65 subunit of NF-κB for histamines effect was elucidated by loss-of-function studies (siRNA). Finally, the effect of histamine on NF-κB binding to the apo A-I gene promoter was examined by chromatin immunoprecipitation. KEY FINDINGS: Treatment of HepG2 cells with histamine had no effect on histamine H1 receptor expression. However, treatment with histamine increased NF-κB p65 and p50 subunit expression significantly. At low levels, the exogenous histamine H1 receptor plasmid suppressed apo A-I gene promoter activity while addition of higher levels of plasmid DNA actually increased apo A-I gene promoter activity. Inhibition of NF-κB activity with SN50 prevented histamine from repressing apo A-I promoter activity as did silencing p65 expression via siRNA. Finally, treatment with histamine increased binding of the p65 subunit of NF-κB to the apo A-I gene promoter. SIGNIFICANCE: Histamine suppresses apo A-I gene expression in hepatocytes via the histamine H1 receptor by elevating NF-κB expression and binding to the apo A-I promoter.

Regulation of the renin-angiotensin system in coronary atherosclerosis: a review of the literature.

Activation of the renin-angiotensin system (RAS) is significant in the pathogenesis of cardiovascular disease and specifically coronary atherosclerosis. There is strong evidence that the RAS has effects on the mechanisms of action of atherosclerosis, including fibrinolytic balance, endothelial function, and plaque stability. Pharmacological inhibition of the renin angiotensin system includes angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and renin inhibitors. These agents have clinical benefits in reducing morbidity and mortality in the management of hypertension. In addition, ACE inhibitors and ARBs have shown to be effective in the management of congestive heart failure and acute myocardial infarction. This review article discusses the biochemical and molecular mechanisms involving the RAS in coronary atherosclerosis as well as the effects of RAS inhibition in clinical studies involving coronary atherosclerosis.

Contrast-induced encephalopathy following coronary angioplasty with iohexol.

We report a case of a patient who developed acute encephalopathy following coronary angioplasty with iohexol contrast. The patient's clinical condition was associated with slowing on the EEG. Studies did not reveal any other etiology or contributing cause for the encephalopathy. The patient recovered spontaneously in 24 hours with only supportive measures. This report suggests that such a drug reaction could occur with iohexol injected in the coronaries, but reassures that the encephalopathy is self limiting.

Revisiting niacin: reviewing the evidence.

Atherogenic dyslipidemia, defined by a cluster of lipoprotein abnormalities, including low high-density lipoprotein cholesterol (HDL-C) and elevated serum triglycerides, represents an important potential target for reducing cardiovascular risk. This has paved the way for revisiting niacin as a therapy in preventing progression of atherosclerosis. Niacin remains the safest and most effective agent for raising HDL-C and is a logical choice to target atherogenic dyslipidemia. While the clinical efficacy of niacin has been known for many years, it is only with development of newer formulations, which have lower side-effect profiles and improved compliance, that the potential for this agent been fully realized. In this review, we will examine some of the reasons that niacin can have important implications for reducing progression of atherosclerosis. We will first examine the different formulations and their variability, not only in side-effect profiles, but also in clinical efficacy. We will then consider the theoretical evidence for the benefit of HDL-raising produced by niacin on atherosclerotic progression. Finally, we will review clinical data suggesting the benefit of niacin on cardiovascular outcomes.

Efficacy of controlled-release niacin in treatment of metabolic syndrome: Correlation to surrogate markers of atherosclerosis, vascular reactivity, and inflammation.

BACKGROUND: The mechanisms that link metabolic syndrome to development of atherosclerosis are largely unknown. There is increasing evidence for the role of adipokines in this process. Niacin would appear to be a logical choice in combating the atherogenic dyslipidemia seen in metabolic syndrome, as it remains the most effective agent in raising high-density lipoprotein cholesterol, and also reduces triglycerides. We hypothesized that statin-intolerant patients with insulin resistance would respond to controlled-release niacin with a rise in plasma adiponectin levels. METHODS: Fifty patients with the metabolic syndrome (National Cholesterol Education Program/Adult Treatment Panel III criteria) were randomized to either once-daily controlled-release niacin (1000 mg/day) or placebo. Measurements at baseline and after 52 weeks of treatment were made of the carotid intimal media thickness, flow-mediated dilation of the brachial artery, and blood plasma adiponectin levels. These measures were compared to changes in lipoprotein concentrations in plasma. RESULTS: Changes in high-density lipoprotein cholesterol correlated significantly to changes in flow-mediated vasodilation and carotid artery intima-media thickness, and there was a trend toward correlation with plasma adiponectin levels. There was a significant difference in mean serum levels of adiponectin after the treatment period between placebo and niacin groups (16.3 ± 1.7 and 17.7 ± 1.9 mg/dL, respectively) (P = 0.022). CONCLUSIONS: Treatment with controlled-release niacin for 52 weeks results in sustained improvements in adiponectin levels compared to placebo in patients with metabolic syndrome. No adverse effects of niacin on glycemic control were found.