Lipoprotein lipase (LPL) is an important enzyme for the hydrolysis of TG on lipoproteins, and its activity is positively correlated with the plasma levels of high density lipoprotein cholesterol (HDL-C). To investigate the association between the LPL gene and low HDL-C levels, we studied two polymorphisms (Hind III and Pvu II) and three mutations (Asn291Ser, Gly188Glu and LPL_Arita) of the LPL gene in 114 children with low HDL-C levels (<40mg/dl) and 194 control children using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) techniques (PCR-RFLP). The frequency of the Pvu II +/+ genotype was significantly higher in the children with low HDL/high TG (TG>100mg/dl, 90th percentile level among Japanese schoolchidren) than in the other children (vs the low-HDL/normal-TG children, x²=7.49, p<0.01 ; vs control children, x²=7.23, p<0.01). PvuII+allele of the LPL gene was associated with elevated TG levels in low HDL-C groups. In addition, we found one heterozygote of LPL_Arita (deletion of G at base 916 in exon 5, the most common mutation of LPL deficiency in Japanese), among the low-HDL/high-TG subjects. The other two variants were not detected in either then low-HDL children or control children. LPL Asn291Ser and Gly188Glu have been presumed to be rare in the Japanese population. In conclusion, our results suggest that hypoalphalipoproteinemia with elevated TG level may be associated with genetic variations of the LPL gene.

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We investigated in vitro effect of simvastatin, a potent 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, on the proliferation of human and bovine endothelial cells (EC) compared to that of bovine smooth muscle cells (SMC). Cells were cultured in a medium supplemented with 10% normal serum (FBS). Simvastatin at concentrations ranging from 0.1 μg/ml to 10 μg/ml were used. In each kind of cells the proliferation was markedly reduced at 1 μg/ml of simvastatin (P<0.01) which was accompanied by morphological changes in the cell shape. We conclude that simvastatin inhibits the proliferation of not only the smooth muscle cells but also the endothelial cells.

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The apolipoprotein (a) [apo (a)] gene encodes a protein component of lipoprotein (a) [Lp (a)] whose plasma levels vary among individuals. To study the implications of Lp (a), we examined plasma Lp (a) levels and molecular weights of apo (a) in patients with cerebrovascular disease (CVD) or diabetes mellitus (DN). Mean Lp (a) concentrations were higher in the CVD cases with atherothrombotic brain infarction than in those with brain hemorrhage and lacunar infarction. Lp (a) levels were lower in the DM cases on diet therapy alone than in those treated with insulin or oral hypoglycemic agents. These results suggest that Lp (a) is thrombogenic and atherogenic, and that insulin may modulate Lp (a) levels. We subclassified the apo (a) gene into four types (A-D) by polymorphisms in the 5'-flanking region. We also measured plasma Lp (a) concentrations and examined expression of the gene by an in vitro assay. Homozygotes of type C had higher Lp (a) levels than those of type D, and the relative expression of type C was higher than that of type D in vitro. Lp (a) levels, however, varied even within the same 5'-allele having similar apo (a) isoforms. Thus, Lp (a) concentrations are genetically determined and may be modified by some hormones and cytokines. When we examined transcript levels for apo (a) by RT-PCR in various normal tissues, apo (a) was strongly expressed in liver while not in thyroid or leukocytes. Small amounts of apo (a) transcript were observed in all other organs and tissues. Apo (a) in these tissues may also play a role in inframmation, tissue remodeling, cell migration, and other physiological functions.

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High density lipoprotein (HDL), an antiatherogenic lipoprotein comprises several subclasses differing in composition and metabolic function. This physiological complexity appears to be matched with the growing number of candidate HDL receptors, since several HDL binding proteins have recently been identified in various tissues. Because these putative receptors may signal different pathways it is important to identify their structure and potential role in HDL metabolism. We review recent progress in the cloning and characterization of HB₂, one of a pair of HDL binding proteins (HB₁ and HB₂) first purified from rat liver. The structure of HB₂ is consistent with a receptor role for this membrane protein and when expressed in cells, increases HDL binding 2 fold. HB₂, minimally present in THP-1 cells, is substantially upregulated in macrophages and appears sensitive to cholesterol loading of these cells. The protein shows high homology with adhesion molecules ALCAM and BEN and the possibility that HDL by binding to HB₂, reduces adhesion induced arterial wall injury, is discussed in the context of the known protective role of HDL against atherosclerosis. The possible functions of HB₂ are also compared with other recently cloned HDL receptors.

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The endothelium modulates the tone of the underlying vascular smooth muscle by releasing relaxing factors, including prostacyclin, nitric oxide (NO), and endothelium-derived hyperpolarizing factor (EDHF). In most types of hypertension, endothelium-dependent relaxations are impaired because of a reduced production and/or action of endothelium-derived NO and EDHF. In essential hypertension, endothelium-dependent relaxations are reduced because of a concomitant release of vasoconstrictor prostanoids (endoperoxides and thromboxane A₂). These prostanoids may be produced in the vascular smooth muscle rather than in the endothelium. The endothelial dysfunction observed in hypertension is likely to be a consequence rather than a cause of the disease, representing premature aging of the blood vessels due to the chronic exposure to the high blood pressure. The endothelial dysfunction can be improved by antihypertensive therapy, favoring the prevention of the occurrence of vascular complications in hypertension.

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HGF is a mesenchyme-derived pleiotropic factor which regulates cell growth, cell motility, and morphogenesis of various types of cells, and is thus considered a humoral mediator of epithelial-mesenchymal interactions responsible for morphogenic tissue interactions during embryonic development and organogenesis. Although HGF is originally identified as a most potent mitogen for hepatocytes, HGF is also belonged to a member of endothelium-specific growth factors. Since endothelial cells are known to secrete various anti-proliferative and vasodilating factors, an agent that promotes seeding or regeneration of endothelium may have potential therapeutic value against vascular smooth muscle cell proliferation. The mitogenic action of HGF on human endothelial cells was most potent among growth factors. Moreover, the presence of local HGF system (HGF and its specific receptor, c-met) was observed in vascular cells and cardiac myocytes in vitro as well as in vivo. Production of local HGF production in vascular cells was regulated by various cytokines including transforming growth factor (TGF) -β and Ang II. Furthermore, HGF may be therapeutic growth factors for the treatment of restenosis after angioplasty and arteriosclerosis oblerance, etc., as gene therapy. On the other hand, serum HGF concentration was significantly correlated with blood pressure. These results suggest that HGF secretion might be elevated in response to high blood pressure as a counter-system against endothelial dysfunction, and may be considered as an index of severity of hypertension. In this review, we discussed the potential role of HGF in cardiovascular disease.

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TF is a major regulator of coagulation and hemostasis. High levels of TF antigen and activity are detected in atherosclerotic lesions, particularly in the advanced lesions. When the plaques are ruptured or eroded, exposure of cellular and extracellular TF to circulating blood play a pivotal role in mediating fibrin-rich thrombus formation leading to acute coronary syndromes. On the other hand, activation of blood coagulation and deficiency of coagulation inhibitors, without endothelial cell denudation, are considered to be an important factor of thrombogenesis in the microcirculation. The imbalance between TF and TFPI seems to be important in promoting fibrin thrombus formation in the lung of endotoxin induced DIC condition.

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