Dyslipidemia is said to be present when lipid or lipoprotein levels lie within a range which is known from epidemiological studies to be associated with secondary complications, in particular atherosclerosis of the coronary arteries, or when a lipid or lipoprotein grossly deviates from the norm as in abetalipoproteinemia, hypobetalipoproteinemia or the HDL deficiency syndromes. In most cases, dyslipidemia is due not to a single genetic or environmental factor, but to a combination of the effects of several genes of small effect (polygenes) and environment. In other cases, however, dyslipidemia is caused by a mutation in a single gene of large effect. In such cases, the extent and nature of the phenotype depends primarily on the identity of the gene involved, but is also modulated to an important degree by the nature of the mutation and the genetic and environmental background against which this mutation occurs. In addition, many cases of hyperlipidemia are secondary to other disorders such as hypothyroidism or renal dysfunction. Such disorders may also unmask or exacerbate a genetic lipoprotein disorder. Examples of the latter are the unmasking of type III hyperlipidemia by diabetes mellitus or the exacerbation of familial hypercholesterolemia by hypothyroidism.
Vascular smooth muscle cell (VSMC) migration and proliferation are believed to play key roles in atherosclerosis. To elucidate the role of vascular dopamine D1-like receptors in atherosclerosis, the effects of dopamine, specific D1-like agonists SKF 38393, and YM 435 on platelet-derived growth factor (PDGF) BB-mediated VSMC migration, proliferation, and hypertrophy were studied. We observed that cells stimulated by 5 ng/ml PDGF BB showed increased migration, proliferation and hypertrophy. These effects were prevented by coincubation with dopamine, SKF 38393, or YM 435 at 1-10 μmol/l, and this prevention was reversed by Sch 23390 (1-10 μmol/l), a specific D1-like antagonist. These actions are mimicked by 1-10 μmol/l forskolin, a direct activator of adenylate cyclase and 8-bromo-cyclic AMP at 0.1-1 mmol/l. The actions are blocked by a specific protein kinase A (PKA) inhibitor N- [2- (p-bromocinnamylamino) ethyl] -5-isoquinoline-sulfonamide (H 89), but are not blocked by its negative control, N- [2- (N-formyl-p-chlorocinnamylamino) ethyl] -5-isoquinoline sulfonamide (H 85). PDGF-BB (5 ng/ml) -mediated activation of phospholipase D (PLD), protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) activity were significantly suppressed by coincubation with dopamine. These results suggest that vascular D1-like receptor agonists inhibit migration, proliferation and hypertrophy of VSMC, possibly through PKA activation and suppression of activated PLD, PKC and MAPK activity.
The molecular mechanisms of the exaggerated growth of vascular smooth muscle cells (VSMC) in hypertension are reviewed based on our previous experimental data. Spontaneously hypertensive rats (SHR) -derived VSMC increasingly express angiotensinogen, cathepsin D and angiotensin-converting enzyme (ACE) mRNAs, compared to cells from normotensive Wistar-Kyoto (WKY) rats, indicating the presence of an Ang II generating system in a homogeneous culture of VSMC from SHR. The produced Ang II then induces TGF-β. SHR-derived VSMC show the distinct expression and abnormal regulation by Ang II of TGF-βreceptors when compared with cells from WKY rats, which express TGF-β type II receptor predominantly to induce PDGF A-chain stimulation of VSMC growth. These findings imply that the increased growth of VSMC in hypertension is a primary event independent of high blood pressure, and is associated with endogenous Ang II-related growth factors.
A decrease in smooth muscle cells is observed in advanced atherosclerotic lesion. To understand this mechanism, we selected oxysterols as candidates for toxic lipid, and examined their cytotoxicity on human cultured vascular smooth muscle cells, together with the manner of cell death. In the presence of 7-ketocholesterol or 7β-hydroxycholesterol (50 μmol/L), the percentage of detached cells increased significantly with dose dependency, and an increase in detached cell number and DNA nick detected by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling study (TUNEL) preceded an increase in lactate dehydrogenase released into the medium. DNA extracted from smooth muscle cells incubated with 7-ketocholesterol or 7β-hydroxycholesterol showed a laddering pattern on agarose electrophoresis. In the presence of 7-ketocholesterol or 7β-hydroxycholesterol, fragmented DNA quantified by the quantitative sandwich enzyme immunoassay was significantly increased. From these results, it is proposed that 7-ketocholesterol and 7β-hydroxycholesterol are toxic to smooth muscle cells, and that this cytotoxicity is mediated by apoptosis.
We have investigated the effects of copper-zinc type superoxide dismutase (Cu, Zn-SOD) on the function of oxidized low density lipoprotein, utilizing cultured smooth muscle cells (SMC), obtained from rabbit aorta. We added native LDL (nLDL), minimally oxidized LDL (MmLDL) and copper ion-induced oxidized LDL (OxLDL) to the culture media. No remarkable change was found out by adding nLDL. The numbers of SMC, including migrated SMC, were increased by the addition of MmLDL. Cu, Zn-SOD significantly inhibited the reactions induced by MmLDL. The SMC numbers were markedly decreased by OxLDL addition without recovery by adding Cu, Zn-SOD. Thus, MmLDL significantly promoted the SMC proliferation and migration. OxLDL revealed strong cytotoxicity against SMC. Cu, Zn-SOD inhibited both the migration and the proliferation of SMC induced by MmLDL, and did not alter the effect of OxLDL. In conclusion, Cu, Zn-SOD inhibited some functions of MmLDL, and may play an important role in protecting against the atherosclerotic processes evoked by MmLDL.
To investigate whether pressor substances accelerate low density lipoprotein peroxidation by Cu++, low density lipoprotein was dialysed against physiological saline containing 0-5 μ mol/1 CuCl2 and/or 1 μmol/l of various pressor substances. Lipid peroxide value of low density lipoprotein changed little with the addition of norepinephrine to the saline, but the addition of norepinephrine to 1 μmol/l CuCl2 accelerated the peroxidation. When low density lipoprotein was dialysed against saline with norepinephrine, epinephrine, serotonin or dopamine, there were no significant differences in the lipid peroxide values of low density lipoprotein. Although the addition of serotonin into the dialyzate did not accelerate the peroxidation of low density lipoprotein due to Cu++, the addition of norepinephrine, epinephrine and dopamine accelerated the Cu++ -peroxidation with a significant increase in the acceleration rate starting at the 36 hour point. Thus, it is speculated that various stresses stimulating the sympathetic nervous system accelerate the peroxidation of low density lipoprotein and produce peroxidized low density lipoprotein in the blood
Our purpose was to determine whether lipid peroxides are elevated in the plasma of patients with non-insulin dependent diabetes with multiple lacunar infarcts as detected by magnetic resonance imaging (MRI), and to confirm whether peroxide levels correlate with glycemic controls and blood lipid levels. The level of lipid peroxide (measured as thiobarbituric acid reactive substances (TBARS)) was measured in 23 healthy controls and 28 diabetics showing normal MRI findings and 22 diabetics with multiple lacunar infarcts. These groups were age-matched. In patients with multiple lacunar infarcts, systolic blood pressure, diastolic blood pressure and TBARS levels were significantly higher than in diabetics without such infarcts (p < 0.05). When the diabetic patients were divided into two groups according to the presence or absence of hypertriglyceridemia or hyperglycemia, in both groups plasma TBARS levels in patients with multiple lacunar infarcts were significantly higher than in patients without such infarcts. Multivariate analysis showed systolic blood pressure and plasma TBARS levels to be independent predictors of multiple lacunar infarcts. Among diabetics, total plasma TBARS levels were positively correlated with fasting blood glucose, HbA1c and triglyceride levels, but not with total cholesterol levels and age. In conclusion plasma lipid peroxides were elevated in diabetics with multiple lacunar lesions, and are related to the metabolic imbalance of plasma glucose and lipids.