Bhalchandra J. Kudchodkar

Hyperbaric Oxygen Reduces the Progression and Accelerates the Regression of Atherosclerosis in Rabbits

We studied the effect of hyperbaric oxygen (HBO) treatment on the extent of diet-induced accumulation of lipid oxidation products in rabbit plasma and tissues, on plasma paraoxonase activity, and on the extent of progression and regression of atherosclerotic lesions in the rabbit aorta. HBO treatment of cholesterol-fed rabbits dramatically reduces the development of arterial lesions despite having little or no effect on plasma or individual lipoprotein cholesterol concentrations. Compared with no treatment in cholesterol-fed animals, HBO treatment also substantially reduces the accumulation of lipid oxidation products (conjugated dienes, trienes, and thiobarbituric acid-reactive substances) in plasma, in the low density lipoprotein and high density lipoprotein fractions of plasma, in the liver, and in the aortic tissues. In addition, HBO treatment prevents the decrease in plasma paraoxonase activity observed in rabbits fed cholesterol-rich diets. Similarly, in regression studies, HBO treatment has no effect on the rate of plasma (or lipoprotein) cholesterol decline but significantly accelerates aortic lesion regression compared with no treatment. Direct measures of aortic cholesterol content support these morphological observations. On the basis of these results, we conclude that repeated, but relatively short, exposure to HBO induces an antioxidant defense mechanism(s) that is responsible for retarding the development or accelerating the regression of atherosclerotic lesions.

Hyperbaric oxygen treatment attenuates the pro-inflammatory and immune responses in apolipoprotein E knockout mice

Chronic hyperbaric oxygen (HBO) therapy significantly attenuates atherosclerosis in New Zealand white rabbits as well as the apoE knockout (KO) mice, independent of plasma lipid concentrations and lipoprotein profiles. Because atherosclerosis has many features of a chronic inflammatory disease, in which both cell-mediated and humoral immune responses participate, we examined the effect of HBO treatment on various aspects of the immune response. We now demonstrate that in apoE KO mice, HBO treatment significantly reduces the circulating levels of antibodies to (MDA)LDL, both in the IgG and IgM class, as well as the delayed-type hypersensitivity (DTH) response to oxLDL challenge. Furthermore, HBO treatment results in a profound attenuation in the production of pro-inflammatory cytokines in response to an inflammatory stimulus (LPS), which is accompanied by a marked increase in the constitutive production of the anti-inflammatory cytokine IL-10 by spleen cells, independent of antigen specificity, as indicated by polyclonal activation of T cells. Our results demonstrate that HBO treatment results in the dampening of T and B cell-mediated responses to oxLDL or inflammatory stimuli.

Effects of Simvastatin on Plasma Lipids and Apolipoproteins in Familial Hypercholesterolemic Swine

Familial hypercholesterolemia (FHC) in swine, which resembles human familial combined hyperlipidemia, is a complex lipid and lipoprotein disorder associated with the development of severe coronary lesions similar to those occurring in advanced human coronary disease. The disorder is characterized by elevated plasma total cholesterol (TC), triglycerides (TG), LDL-cholesterol (LDL-C), apolipoproteins (apo) B, C-III, and E, and by decreased levels of HDL-cholesterol (HDL-C), apoA-I, and lecithin:cholesterol acyltransferase (LCAT) activity. A dose-response study with simvastatin, a specific inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, was conducted in four treatment groups of FHC animals, exhibiting TC > or = 250 mg/dL. The animals were fed 0, 80, 200, or 400 mg simvastatin daily for 3 weeks. The measured serum parameters included the levels of TC, VLDL-C, LDL-C, HDL-C, TG, lathosterol, apoA-I, B, C-III, and E, as well as LCAT activity. Simvastatin at 200 mg/d significantly decreased the levels of TC (-25%), LDL-C (-27%), lathosterol (-40%), apoB (-22%), apoC-III (-37%), and apoE (-24%) and modestly decreased the levels of HDL-C (-12%) and apoA-I (-11%) (percent relative to the average pretreatment and posttreatment baseline values) but did not affect the levels of TG, VLDL-C, the lathosterol/TC ratio, or LCAT activity. The levels of TC, LDL-C, apoB, and E were also lowered by simvastatin at 80 or 400 mg/d, but to a lesser extent than at 200 mg/d, while the other parameters were not influenced at these doses. The simvastatin-induced decreases of LDL-C, HDL-C, and apoA-I, B, C-III, and E were significantly correlated among each other. These results show that the trend of responses in TC, LDL-C, apoB, apoC-III, and apoE to simvastatin in the FHC swine is similar to that observed in humans, although the drugs is less potent and efficacious in swine, while the results are different from those in humans with regard to the remaining parameters.

High cholesterol diet down regulates the activity of activator protein-1 but not nuclear factor-kappa B in rabbit brain.

Cardiovascular risk factors and alterations in cholesterol metabolism are implicated in the pathogenesis of Alzheimers dementia (AD). The hypercholesterolemic rabbit model of atheroslerosis and AD was utilized in this study to examine oxidative stress related changes in the brain. The high cholesterol diet induced dramatic increases in plasma and liver cholesterol concentrations, but brain cholesterol levels remained constant. Similar effects have been found regarding lipid oxidation products. The amounts of conjugated dienes, trienes and thiobarbituric acid reactive substances (TBARS) significantly increased in the plasma of cholesterol treated animals while the brain cortex showed no signs of increased lipid peroxidation. The oxidative damage sensitive nuclear transcription factor kappa B (NF-kappaB) and activator protein-1 (AP-1) diverged in their responses. Accordingly, the AP-1 DNA binding activity decreased by more than 50% in brain nuclear protein extracts while the NF-kappaB binding activity remained unaltered by the hypercholesterol diet. These results indicate that despite the relative resistance of the central nervous system to dietary manipulation of its lipid composition and lipid peroxidation products, chronic dietary intake of cholesterol can alter the function of certain proteins involved in regulation of gene expression in the brain.

Evaluation of gemfibrozil therapy: predictive response from lipoprotein subfraction analysis.

Subjects with high-density lipoprotein cholesterol (HDL-C) values of less than 47 mg/dL (mean 35.6 ± 5.5 mg/dL) were selected for this study to examine relationships between plasma lipids, lipoprotein components, and the outcome of gemfibrozil therapy. Changes in plasma lipoprotein sub-fractions were determined to better understand the previously observed variability of the responses in both HDL-C and triglycerides to gemfibrozil. Based on the data collected, an attempt was made to identify pretreatment lipid parameters that may be predictive regarding the efficacy of gemfibrozil therapy. Serum samples were analyzed at the outset and after the conclusion of 12 weeks of gemfibrozil therapy. Because the HDL-C response to therapy was highly variable, the data from patients were separated into two groups, responders (>20% increase in HDL-C) and nonresponders (<20% increase in HDL-C). The lipid components of lipoprotein subfractions were evaluated using multiple regression analysis yielding predictive models that show the relationship between specific lipoprotein subfractions and the percentage change in HDL-C and posttreatment triglyceride levels. Group classification was then predicted with 78% accuracy using specific lipoprotein subfractions to estimate an individuals percentage change in HDL-C. The major difference between the responder and nonresponder groups was their respective correlations between triglyceride-lowering and changes in HDL-C. In the responder group, there was a significant correlation between the changes in HDL-C and the lowering of triglycerides (r = 0.61, p = 0.03), whereas the nonresponder group showed no such correlation (r = 0.17, p = 0.52). The predictive model also proved to be highly accurate in forecasting the effectiveness of the triglyceride-lowering action of gemfibrozil in this group of patients.

Decrease in high density lipoprotein cholesterol (HDL-C) levels following gemfibrozil therapy

Abstract This report represents the continuation of our studies on the effects of gemfibrozil therapy on high density lipoprotein cholesterol levels. Previously, we reported that despite an impressive mean increase in high density lipoprotein cholesterol (20 %), the response to 12 weeks of gemfibrozil therapy was highly variable. Accordingly, out of the 27 subjects studied, five actually had lower high density lipoprotein cholesterol at the conclusion of therapy compared to baseline values. The changes observed in plasma lipids, combined with correlational relationships suggest that the conversion of triglyceride rich lipoprotein components into high density lipoprotein may be impaired in those subjects that respond poorly or negatively to gemfibrozil therapy.