Atherosclerosis is primarily a lesion that progresses due to a series of reactions that are induced by repair of injured intima. The intercellular networking that occurs among smooth muscle cells, macrophages, T lymphocytes and endothelial cells leads to a fibroproliferative response, in which the extracellular matrix (ECM) plays an important role. The ECM, composed of a mixture of vastly different macromolecules including collagen, elastin, glycoproteins and proteoglycans, confers tensile strength and viscoelasticity to the arterial wall. Each component of the ECM possesses unique structural properties that determine its own roles during the development of atherosclerotic plaques. Not only does the ECM provide the structural integrity of the plaques, but it also participates in several key events such as cell migration and proliferation, lipoprotein retention and thrombosis. The various matrix metalloproteinases (MMPs), major enzymes in ECM degradation, and their inhibitors (tissue inhibitors of MMPs) are demonstrated in plaque. An excess of MMPs over inhibitors contributes significantly to ECM destruction rendering the plaque more prone to rupture. Accumulating information on the molecular regulation of ECM synthesis and degradation will help investigators attain a more thorough understanding of the mechanisms of plaque formation and plaque instability and rupture.
Vascular remodeling, defined as lasting structural changes in the vessel wall in response to hemodynamic stimuli, plays a role in many (patho)physiological processes requiring cell migration and degradation of extracellular matrix(ECM). Matrix metalloproteinase(MMP) system can degrade most ECM components. Several lines of evidence support a role for MMP system components in the development and progression of atherosclerosis and restenosis after angioplasty. This review article focuses on the role of MMPs in vascular remodeling relevant to atherosclerosis and restenosis after angioplasty.
A serum lipoprotein(a) (Lp(a)) is an independent risk factor for cardiac events. It is well known that the patients with chronic renal failure (CRF) have a high concentration of serum Lp(a). The purpose of this study was to indicate the relationship between serum Lp(a) concentration and apoprotein(a) (apo(a)) isoforms under the condition of renal dysfunction. One-hundred thirty patients having hypertension, hyperlipidemia, diabetes mellitus and/or CRF were selected in this study. All patients were divided into two groups according to the level of serum creatinine. Serum Lp(a) concentration in the CRF patients (Cr > 2.0 mg/dl) was significantly higher than that in the controls (Cr < 1.2 mg/dl). Many CRF patients had high molecular weight (HMW)-apo(a). This study showed that the increase in HMW-apo(a) was closely accompanied by the increase in serum creatinine levels, and the serum Lp(a) concentration with HMW-apo(a) was higher according to their creatinine levels.
We found previously that the ingestion of margarine containing medium-chain triacylglycerols (MCT) resulted in a significant increase in postprandial thermogenesis when compared with long-chain triacylglycerols (LCT). Diets that included margarine containing MCT and LCT were compared for 12 weeks in 73 subjects to investigate the effects on body weight, body fat, areas of subcutaneous and visceral fat, serum total cholesterols, triglycerides, lipoproteins, plasma glucose, serum insulin, total ketone bodies, and the activities of aspartate aminotransferase, alanine aminotransferase, and γ-glutamyltranspeptidase. We conducted a double-blind, controlled study and used blended rapeseed oil and soybean oil (LCT) as a comparison. Two groups ingested 2, 100−2, 400 kcal/day of energy, 65−73 g/day of total fat, and 14 g/day of test margarine (5 g/day of MCT or LCT). The subjects on the MCT diet demonstrated significant decreases in body fat weight (− 3.8 ± 2.4 kg vs − 2.4 ± 1.7 kg; MCT vs LCT, mean ± SD), subcutaneous fat (− 38.2 ± 29.9 cm2 vs − 22.6 ± 19.3 cm2), and visceral fat (− 12.2 ± 11.2 cm2 vs − 1.6 ± 12.8 cm2) after 12 weeks. There were no clinical differences in measured blood parameters. We suggest that the postprandial increase in thermogenesis and control of postprandial triglyceride levels may explain these results.
The purpose of this study was to screen for FCHL in children using serum lipid phenotypes. The subjects were 1, 190 (599 male, 591 female) children who participated in a screening and care program for life style-related diseases in school children. Total cholesterol, high-density lipoprotein cholesterol and triglyceride were determined, and information on the family history of parents was obtained by questionnaire. Candidates for FCHL were screened by the following criteria; type IIb hyperlipidemia, type IIa hyperlipidemia with positive family history of CHD, hyperlipidemia or both. We informed them of the results by mail. A second series of examinations to diagnose FCHL was performed on volunteer participants, including their parents. The candidates consisted of 9 children with type IIb and 27 with type IIa hyperlipidemia, 11 of whom participated, in the second series of examinations, in which 5 children were diagnosed with FCHL. The prevalence was 0.4%, suggesting that at least half of all individuals with FCHL already demonstrate hyperlipidemia in childhood.
DNA microarray gene expression analysis was conducted in human umbilical vein endothelial cells (HUVECs) and coronary artery endothelial cells (HCAECs) exposed to laminar or turbulent shear stress. Approximately 3% of the total 5600 gene in HUVECs and HCAECs increased their expression more than two-fold or decreased it to less than half the static control in response to an arterial level of laminar shear stress (15 dynes/cm2 for 24 hours). The proportions of shear-stress-responsive genes decreased to around 2% under the venous level of laminar shear stress (1.5 dynes/cm2) in both cell lines. Turbulent shear stress of 1.5 dynes/cm2 altered the expression of 1.1% of all genes in the HCAECs. Laminar shear stress, but not turbulent shear stress, decreased the expression of a number of genes involved in DNA synthesis and the cell cycle in both HUVECs and HCAECs. Clustering analysis showed a variety of temporal profiles of gene expression in HUVECs exposed to laminar shear stress of 15 dynes/cm2 for 3, 6, 12, 24, and 48 hours. Turbulent shear stress affected expression of many genes that play a role in vascular remodeling, including genes encoding plasminogen activators and their inhibitor, endothelin-1, transforming growth factor-β, collagen type IV, and ephrin A1.
The objective of this study was to estimate postprandial hypertriglycemia by a newly designed oral fat-loading test. Twenty-three healthy normolipidemic volunteers were orally administered a test meal consisting of a mixture of Telmeal 2.0® and 20 g of salt-free butter after fasting for 12 h. To measure the levels of total cholesterol (T-Cho), triglycerides (TG), high-density lipoprotein-cholesterol (HDL-C), remnant-like particle-cholesterol (RLP-C), lipoprotein (a) [Lp (a)], free fatty acid, apolipoproteins (Apos), plasma glucose (PG), immunoreactive insulin (IRI), and high-sensitivity C-reactive protein (hs-CRP), venous blood samples were collected before the meal and at each hour until 9 h after fat-loading. The levels of both TG and RLP-C were drastically elevated at 2 h after fat-loading and these levels remained high until 4 h (p < 0.01). A significant correlation between TG and RLP-C was also observed at 2, 3 and 4 h, and the values of the correlation coefficients (r) were 0.837, 0.838, and 0.908, respectively. In contrast, the levels of T-Cho, HDL-C, Lp (a), Apos, PG, and hs-CRP did not change. Furthermore, there were no gastrointestinal symptoms during or after the study. These results strongly suggested that this newly designed fat-loading test was very useful for evaluating postprandial hypertriglycemia, including remnant concentrations.
A 77-year-old woman with type II diabetes mellitus was admitted to our hospital in August/ 1995 with severe hyperlipidemia. She had taken feedings through a nasogastric tube with 1, 000 ml (1, 000 kcal) of Ensureliquid® daily since 1993 because of the muscle weakness after rhabdomyolysis. Her serum total cholesterol was 515 mg/dl and triglyceride was 3, 378 mg/dl despite administration of 10 mg of simvastatin daily. After substitution of a standard diet starting August 21, we found significant decreases of total cholesterol from 725 mg/dl to 194 mg/dl and triglyceride from 4, 680 mg/dl to 550 mg/dl within 37 days. We also found a severe decrease in her serum total carnitine level of 22 μmol/l (normal range 45−91 μmol/l) before changing the diet, suggesting secondary carnitine deficiency. Severe hyperlipidemia was reversed by changing the carnitine deficient diet (Ensureliquid®) to a carnitine-containing diet. We suggested that the development of hyperlipidemia was related to the carnitine deficiency.