Experimental autoimmune myocarditis (EAM) in rats is an animal model of human giant cell myocarditis and postmyocarditis dilated cardiomyopathy. As the heart consumes large amounts of energy, heart diseases such as myocarditis and dilated cardiomyopathy are associated with abnormal fatty acid metabolism. Peroxisome proliferator-activated receptor α (PPARα) is a regulator of the oxidative degradation of fatty acids. To investigate the role of PPARα in EAM, fenofibrate (a PPARα activator) was administered to rats with EAM for 4 weeks. Reductions in the ratios of both ventricular weight to body weight and the area of inflammatory lesions to the total area of heart sections were observed in fenofibrate-treated rats when compared with controls. Fenofibrate ameliorated changes in serum albumin and sialic acid, which are markers of inflammation. Cardiac expression of interleukin-10 (IL-10) mRNA was more pronounced in the fenofibrate group than in the control group (1.3±0.2 vs 0.7±0.1; p<0.01), and the area of intact myocardium correlated with the IL-10 mRNA level (p=0.0297, r=0.620). We suggest that PPARα activators may prevent the progression of myocarditis through increased expression of the gene encoding the anti-inflammatory cytokine IL-10, although the mechanisms involved remain to be determined.
Apolipoproteins in the cerebrospinal fluid (CSF) play important roles in lipid metabolism in the central nervous system. Although it has been demonstrated that apo E is synthesized in the neuron, the synthesis of apo A-I has only been determined in fish and chicken. It was demonstrated that apo A-I concentrations in the CSF were increased in poliovirus-infected macaques, however, the origin of the CSF apo A-I was not determined. The present immunohistochemical study provided evidence that apo A-I was localized within the nerve cell body of the rat spinal cord. In situ hybridization also showed that apo A-I mRNA was predominantly expressed in the neurons. As a further experiment, we compared apo A-I levels in the spinal cord from control rats and rats with experimental allergic encephalomyelitis (EAE), which was induced by sensitization with myelin basic protein. Although no significant changes in serum apo A-I levels were observed, apo A-I levels in the spinal cord were significantly elevated in EAE rats. Furthermore, apo A-I in the spinal cord of rats with EAE was not seen in the nerve cell body, but at the interstitium, particularly in lesions where inflammation had occurred. The current study clearly demonstrated that apo A-I is synthesized in the neurons of the rat spinal cord and the synthesis was suppressed in EAE rats.
The Chiba Lipid Intervention Program (CLIP) Study was designed to clarify the prognosis of Japanese hypercholesterolemic patients taking pravastatin for 5 years. Hypercholesterolemic patients (n=2, 529) with a total cholesterol level ≥220 mg/dl and without histories of ischemic coronary heart disease and/or cerebral infarction were administered pravastatin (10-20 mg/day). Among them, 2, 131 took pravastatin fully (Pravastatin-continued group), and 398 discontinued the treatment (Discontinued group). The baseline total cholesterol level was 264.3±34.7 mg/dl (mean±standard deviation). The mean reduction rates of total cholesterol and low-density lipoprotein (LDL) cholesterol were 18.0% and 27.2%, respectively. Mild and moderate adverse events occurred in 86 cases (3.6%). Serious adverse events were not observed. Death rates of the pravastatin-continued group and of the discontinued group were 2.6 and 16.0/1, 000 persons/year, respectively. Cardiac events (fatal and nonfatal myocardial infarction, cardiac death, angina pectoris) in all, occurred in 35 patients (incidence rate=2.77/1, 000 persons/year). In the pravastatin-continued group, 9 causes of fatal and nonfatal myocardial infarction occurred (0.84/1, 000 persons/year), whereas in the discontinued group, 4 cases occurred (2.06/1, 000 persons/year). The risk ratio for cardiac events was correlated with the number of risks. In the low-risk group (≤1 risk), decreased rates of LDL-cholesterol were less in the cardiac event group than the non-cardiac event group (LDL-cholesterol; 16% vs 25%, p=0.04). These results suggested the following; 1) Pravastatin maintained a cholesterol lowering effect long-term without serious complications. 2) Pravastatin administration might reduce the mortality rate and myocardial infarction. 3) The combination of multiple risks is a strong factor for a cardiac event in addition to hypercholesterolemia.
In advanced atherosclerotic lesions, a decrease in smooth muscle cells is observed in the cap tissue. This causes the thinning of the cap, and may lead to plaque rupture. We studied the effect of deposited lipids on the migration of vascular smooth muscle cells, and identified the main cause of the effect. The lipids were extracted from atherosclerotic lesions in the human aorta at autopsy, and separated into three fractions with a Sep-Pak ODS cartridge. Then, each fraction was added to the lower part of a chemotaxis chamber, and cultured vascular smooth muscle cells to the upper part. After 4 hours incubation, the cells that had migrated to the opposite side were counted. The oxysterol-rich fraction (10 μg/ml) inhibited the migration, whereas the cholesterol ester and free cholesterol fractions did not. Finally, we tested the pure oxysterols, 7-ketocholesterol and 27-hydroxycholesterol. Both inhibited migration, whereas the free cholesterol and cholesterol ester did not. Oxysterols generated in the lipid pool might inhibit the migration of smooth muscle cells.
This study examined the ability of sweet elements extracted from Siraitia grosvenori (SG) to inhibit the oxidation of LDL. We monitored the formation of conjugated diene during copper-mediated LDL oxidation in the presence or absence of sweet elements of whole extract of SG (SG extract) or cucurbitane glycosides (CGs) purified from SG extract as sweet elements. CGs consist of Mogroside IV (Mog.IV), Mogroside V (Mog.V), 11-Oxo-mogroside V (11-Oxo-mog.V), and Siamenoside I (Sia.I). In addition, the effect of these elements on human umbilical vein endothelial cell (HUVEC)- mediated LDL oxidation was tested by measuring production of lipid peroxides. SG extract inhibited copper-mediated LDL oxidation in a dose-dependent fashion, but neither glucose nor erythritol suppressed the oxidation. Among CGs, 11-Oxo-mog.V significantly inhibited LDL oxidation, and prolongation of the lag time during LDL oxidation by 11-Oxo-mog.V was dose-dependent. The lag time (119.7±8.9 min) in the presence of 200 μM 11-Oxo-mog.V was significantly longer than that (76.8±5.5 min) of control (p<0.01). In addition, SG extract and 11-Oxo-mog.V inhibited HUVEC-mediated LDL oxidation in a dose-dependent manner. These results demonstrate that SG extract can inhibit LDL oxidation and that 11-Oxo-mog.V, a sweet element of SG extract, provides the anti-oxidative property of SG which might reduce the atherogenic potential of LDL.
The present study was performed to clarify the relation between plasma homocysteine and ischemic stroke. We studied the relationship between ischemic stroke and the known risk factors for atherosclerosis including plasma homocysteine in 91 in-patients (80.3±6.8 years) in a medical ward. Those diagnosed with transient ischemic attack, cerebral infarction were placed in the disease group. Blood was drawn from in-patients in a fasting state for determination of plasma homocysteine. Plasma homocysteine concentrations were determined using a high-performance liquid chromatography assay. The odds ratio of ischemic stroke was higher in the second (10.0-13.9 μmol/l) and third highest plasma homocysteine concentration groups (≥14.0 μmol/l) than in the first group (<10.0 μmol/l) by 5.18 and 4.42-fold, respectively. Logistic regression analysis using ischemic stroke as an object variable, adjusted by various risk factors including the plasma homocysteine concentration showed that the odds ratio on combining the second and third groups was 5.80 (95% confidence interval (Cl): 1.50-22.5) compared with the first group. The findings confirmed that the association between plasma homocysteine concentration and ischemic stroke in Western populations is also present among the elderly Japanese.