Diet Induced Mild Hypercholesterolemia in Pigs: Local and Systemic Inflammation, Effects on Vascular Injury – Rescue by High-Dose Statin Treatment

Abstract

ObjectiveThe aim of the present study was to comprehensively evaluate systemic and local inflammation as well as progression of vascular inflammation in normal and mechanically injured vessels in a large animal model of mild hypercholesterolemia. Our aim was also to test the effect of high-dose statin treatment on these processes.MethodsPigs were kept for 120 days on a standard diet (SD, n=7), high-cholesterol diet (HCD, n=7) or high-cholesterol diet with Atorvastatin starting after 50 days (STATIN, n=7). Left carotid artery balloon injury was conducted in all groups after 60 days of diet treatment. Biochemical analysis together with evaluation of blood and tissue markers of vascular injury and inflammation were performed in all groups at the end of experiment.ResultsHCD compared to SD induced systemic inflammation demonstrated by increased number of circulating monocytes and lymphocytes. HCD compared to SD induced also local inflammation demonstrated by adipocyte hypertrophy and infiltration of T-lymphocytes in abdominal white adipose tissue, activation of hepatic stellate cells with infiltration of T- and B-lymphocytes and macrophages in the liver and increased macrophage content in lung parenchyma. These changes were accompanied by increased Intima/Media thickness, stenosis, matrix deposition and activated T-cell infiltrates in injured but not in uninjured contralateral carotid artery as we previously reported. The treatment with high-dose statin attenuated all aspects of systemic and local inflammation as well as pathological changes in injured carotid artery.ConclusionsDiet related mild hypercholesterolemia induce systemic and local inflammation in the liver, lung and adipose tissue that coincide with enhanced inflammation of injured vessel but is without deleterious effect on uninjured vessels. High dose statin attenuated systemic and local inflammation and protected injured vessels. However, finding exact role of reduced systemic and remote inflammation in vascular protection requires further studies.

Serum Midkine Levels in Patients with Psoriasis

“…We could consider that higher levels of serum MK might be a useful clue to distinguish psoriatic patients who may have metabolic syndrome in order to make further work up, since metabolic syndrome generally shows elevated triglyceride concentration. 19,20 We did not find any correlation between serum MK level and PASI. Of note, it has been shown in many studies that PASI is not correlated with metabolic syndrome.…”

HDL-Mediated Protection of Coronary Vasodilator Response to Adenosine in the Hypercholesterolemic Swine

“…A higher elevation (about tenfold) of total cholesterol and its fractions was observed in our experiments compared to other studies where hypercholesterolemic diets of similar fat and cholesterol composition were used in swine models of atherogenesis [40]. However, reports, where a lower cholesterol supplement for a longer diet period is also able to ensure an almost tenfold LDL elevation [41], suggest that the relation between cholesterol addition to diet, or duration of diet and the increase of total cholesterol and its lipoprotein-fractions in plasma is not direct.…”

“…To clarify these results a primary role of increased hepatic synthesis of HDL in alternate diet regimen and a better adaptation of liver metabolism to plasma lipid overload as compared to continuous cholesterol administration can be reasonably sustained [42]. Regarding systemic inflammatory state and endothelial activation no significant changes among groups were evidenced in any of measured markers, in contrast with other reports [40] [43]- [45]. This outcome can be attributed to the shorttime diet duration and the very early stage of coronary atherogenesis process documented by histology.…”

“…In fact, a so high LDL plasma level in this study was reached independently of diet duration, being comparable in HF and IHF groups and it can be likely attributed to liver lipid metabolism adaptations to an excessive cholesterol intake. The same considerations can be done for HDL elevation: a great variability is present in different studies of swine hypercholesterolemia [40] [41]. To clarify these results a primary role of increased hepatic synthesis of HDL in alternate diet regimen and a better adaptation of liver metabolism to plasma lipid overload as compared to continuous cholesterol administration can be reasonably sustained [42].…”

Histone acetylation regulates orphan nuclear receptor NR4A1 expression in hypercholesterolaemia

“…Linear regression analysis further demonstrated that plasma levels of cholesterol and LDL-C significantly increase age-and sex-adjusted Lg-NR4A1 mRNA expression. The reasons behind the same effect of cholesterol and LDL-C on NR4A1 expression are clear primarily because LDL is the major plasma carrier of cholesterol in the form of cholesterol ester [40], and plasma levels of LDL-C are generally consistent with the concentration of cholesterol in human plasma.…”