Monocyte chemoattractant protein-1 (MCP-1) has been shown to play an essential role in the pathogenesis of arteriosclerosis and other vascular diseases, such as restenosis after arterial injury, by recruiting monocytes into the arterial wall. We devised a new strategy for anti-MCP-1 gene therapy against arteriosclerosis by transfecting an amino-terminal deletion mutant (7ND), which lacks the amino-terminal amino acids 2 to 8 of the human MCP-1 gene, into a remote organ (skeletal muscles). Intramuscular transduction with the mutant MCP-1 gene suppressed inflammatory and proliferative changes and arteriosclerosis formation induced by the chronic inhibition of nitric oxide synthesis in rats. 7ND gene transfection also inhibited the initiation, progression, and destabilization of atherosclerosis in Apolipoprotein E-knockout mice. Moreover, the strategy reduced restenosis after balloon injury in rabbits, rats, and monkeys, or neointimal formation after stent implantation in monkeys. This new strategy may be a useful and feasible gene therapy against atherosclerosis and restenosis after angioplasty.
The increased frequency of small, dense LDL is associated with the risk of coronary heart disease (CHD). Possible mechanisms include the increased susceptibility of small, dense LDL to oxidation and its high affinity for LDL-receptor-independent cell surface binding sites. Although more than 30% of adult men in the USA have been reported to have small, dense LDL, only 5.4% of young Japanese men are affected. However, more than 76% of Japanese diabetics with coronary heart disease have small, dense LDL. Furtherrmore, almost half of all obese women (BMI > 35 kg/m2) have small, dense LDL. Our previous observation revealed that type 2 diabetics had smaller LDL even if they were apparently normolipidemic. In the normotriglycelidemic group there was also a close relationship between LDL size and plasma triglyceride. Diabetics with microalbuminuria had smaller LDL than those with normoalbuminuria, indicating the early nephrotoxicity of small, dense LDL. We also found that young men with high-normal blood pressure have smaller LDL than those with optimal blood pressure. Furthermore, LDL size was decreased not only in preeclamptic women but also in normal pregnant women. Finally, weight reduction by obese women through strict diet control, the treatment of diabetics by acarbose or troglitazone, and the treatment of hyperlipidemia by new statins as well as fibrates were all successful in increasing LDL size associated with decreased plasma triglyceride.
It is surprising that only about ten years after the concept of insulin resistance in diabetes mellitus was established, the role of insulin resistance in the development of atherosclerosis has been discussed and clarified. Insulin resistance predisposes the development of glucose intolerance, hyperlipidemia, and hypertension; the cluster of these abnormalities is referred to as multiple risk factor syndrome and it increases the risk of atherosclerosis. A few insulin sensitizers have recently begun to be used in the therapy for diabetic patients. However, the inhibitory effects of these insulin sensitizers against atherosclerosis have not been studied in large-scale clinical trials because these drugs were approved for clinical treatment only several years ago. Accordingly, this review presents a summary of the previous studies on the anti-atherogenic effects of insulin sensitizers by different strategies and provides information on why it is expected that insulin sensitizers will be used as anti-atherogenic drugs.
In a study population, we compared the level of malondialdehyde-modified LDL (MDA-LDL) with the concentrations of lipid parameters in serum and found a strong correlation between MDA-LDL and apolipoprotein B (apo B) concentrations. Their interrelations had a turning point at an apo B concentration of 1,150 mg/l. In diabetic patients, the ratio of MDA-LDL/apo B increased at apo B concentrations above 1,150 mg/l. This ratio represents the extent of modification of apo B by MDA. In the control subjects, this ratio remained stable. When we divided the patients into medication groups (statins and insulin), we found that the 1,150 mg/l threshold disappeared. At apo B concentrations above 1,150 mg/l, the ratio of MDA-LDL/apo B in the statin group was as high as that in the non-drug group. In the insulin group, the means of MDA-LDL/apo B in all ranges of apo B levels decreased to an extent statistically indistinguishable from those of the control group. In conclusion, insulin therapy represses LDL oxidation even at apo B concentrations > 1,150 mg/l and should be noted for its anti-oxidation properties.
Atheromatous embolism is a systemic disease resulting from cholesterol crystal embolization in many organs, including the kidneys. To characterize atheroembolic renal disease (AERD), we retrospectively evaluated 11 patients with acute renal failure after vascular surgery, vascular radiology investigations, and anticoagulation at Miyazaki Medical College from 1994 to 2001. The diagnosis of cholesterol atheromatous embolism was confirmed by tissue examination or clinical grounds. The patients were all elderly men (average age of 66.8 years) with a history of hypertension (55%), diabetes mellitus (45%), hyperlipidemia (45%), and coronary artery disease (18%). Seven patients had livedo reticularis, and 4 had blood eosinophilia. Clinically, 7 patients were managed conservatively and 5 of them improved, whereas 4 patients required dialysis and developed chronic renal failure or died. The serum creatinine levels of the improved patients were significantly lower (1.28+/−0.3 mg/dl, p < 0.005) than the non-improved ones (7.70+/−3.6). The number of eosinophils was significantly higher in the improved patients (576+/−295/ml, p < 0.05) than in the non-improved ones (208+/−206). However, no significant difference was observed in the levels of serum cholesterol and C-reactive protein among these patients. Since the population at risk for AERD is growing, we should recognize this disease as a cause of acute renal failure.
Vascular calcification is a common feature of advanced atherosclerosis resulting in reduced elasticity of elastic arteries. However, the relationship between elastic fibers and vascular calcification at the molecular and cellular levels remains unknown. We investigated the expression of major elastic fiber components such as tropoelastin (TE) and fibrillin-1 (FBN1) and elastin-related enzyme, lysyl oxidase (LO), in a calcification model using β-glycerophosphate (β-GP) in cultured bovine aortic smooth muscle cells (BASMCs). Ten mM of β-GP stimulated calcium deposition in a time-dependent manner. As determined by Western blot analysis, 10 mM of β-GP time-dependently decreased TE and FBN1 protein levels. TE, FBN1, and LO mRNA levels, assessed by reverse transcription-polymerase chain reaction, were also decreased by exposure to 10 mM β-GP. Furthermore, we investigated whether the processes of calcification in BASMCs directly control these regulations. In experiments using levamisole, an alkaline phosphatase inhibitor, and DMDP, a bisphosphonate, both inhibitors inhibited down-regulation during β-GP-induced calcification, suggesting that the down-regulation of TE, FBN1, and LO directly relates to calcium deposition. In cases of vascular calcification, the decreased expression of TE, FBN1, and LO may be partially responsible for decreased vascular elasticity and also for the decreased formation of new elastic fibers.
To clarify the influence of a westernized lifestyle on the risk factors for atherosclerosis and preclinical atherosclerosis in Japanese subjects, we surveyed a Japanese population and Japanese immigrants in the United States. Based on the extent of westernization of their lifestyle, the subjects were classified as Japanese (J), first generation Japanese-Americans (JA-I), and second or later generation Japanese-Americans (JA-II). The consumption of animal fat and simple carbohydrates increased in the order of J, JA-I, and J-II, while the subjects with strenuous physical activity decreased in the same order. The waist-hip ratio, fasting insulin level, serum cholesterol and triglyceride levels, and prevalence of hypertension increased in the same order as the dietary changes. The carotid intima-media wall thickness and the plaque size, which are indices of preclinical atherosclerosis, also increased in the order of J, JA-I, and JA-II. These data indicate that a westernized lifestyle aggravates the risk factors for atherosclerosis and influences the progression of preclinical atherosclerosis, in correspondence with the extent of westernization.
Elevated intermediate-density lipoprotein (IDL), a remnant lipoprotein, is an independent risk factor for atherosclerosis in patients with end-stage renal disease (ESRD). Since the presence of diabetes mellitus further increases the risk of cardiovascular mortality in ESRD, we examined the effect of diabetes on IDL among ESRD patients. The subjects were 330 healthy control subjects and 287 patients with end-stage renal disease including 80 patients with type 2 diabetes. As compared with the healthy subjects, the nondiabetic ESRD patients had increased plasma triglyceride and IDL cholesterol. Diabetic patients with ESRD showed a further increase in plasma triglyceride and IDL cholesterol compared with the nondiabetic group. However, the difference in IDL levels between the ESRD groups was no longer significant when subjects were stratified by plasma triglyceride. Plasma triglyceride was correlated with IDL cholesterol. Increased hemoglobin A1c was significantly associated with IDL cholesterol in a multiple regression model including age, gender, and the presence of ESRD. Such an association was no longer significant in another model including plasma triglyceride as an additional covariate. Further analysis indicated the positive effects of diabetes and hyperglycemia on plasma triglyceride. These results indicate that increased IDL in ESRD is further deteriorated in the presence of diabetes, and that the adverse effect is accounted for at least partly by hypertriglyceridemia associated with chronic hyperglycemia.
It is not easy to make diagnose FCHL in children, since a clear expression of lipoprotein abnormality is unlikely and standard criteria have not yet been established. We investigated eight cases of childhood FCHL and their families with respect to familial history, anthropometric parameters and serum lipoprotein levels, to explore the characteristics of childhood FCHL. To diagnose childhood FCHL it is necessary to clarify both the family history and lipid profiles of the parents. In this study, two prominent features were suggested; that serum TG level is affected by both obesity and age, and also in particular, that a significantly elevated level of serum apoB is a predominant feature of FCHL in childhood. It was found that hyperapoB may be revealed antecedently without other lipid abnormalities at an early age. Regardless of other lipoprotein abnormality, it was suggested that hyperapoB might be added to the early diagnostic criteria for FCHL.