Intimal hyperplasia is a key lesion for various vascular disorders such as atherosclerosis, postangioplasty restenosis and transplant arteriopathy. It has widely been accepted that intimal smooth muscle cells (SMC) originate from the medial layer in the same artery. However, recent studies suggest that bone marrow can also provide circulating progenitors for vascular SMC. Bone marrow-derived SMC participate in neointimal formation in animal models of allotransplantation, severe mechanical injury and hyperlipidemia-induced atherosclerosis. In human, transplantation arteriopathy also seems to involve circulating SMC, but their role in atherosclerosis and restenosis remains to be elucidated. Mobilization, differentiation and proliferation steps of SMC progenitors will provide promising targets for novel therapeutic approaches against proliferative vascular diseases.
Thrombin is one of the key molecules involved in the development of vascular diseases. Thrombin does not only serve as a coagulation factor, but it also exerts cellular effects by activating protease (proteinase)-activated receptors (PARs), a family of seven-transmembrane G protein-coupled receptors. This study focused on the role of PARs in the vascular system. Among the four members so far identified, PAR-1 and PAR-2 were found to play an important role in the vascular system, while the functional roles of PAR-3 and PAR-4 appear to be mostly limited to platelets. The endothelial cells play a primary role in mediating the vascular effects of PARs under physiological conditions, while PARs of the smooth muscle cells can be induced under pathological conditions, and therefore play a more pathophysiological role. PAR-1 and PAR-2 mediate various vascular effects including regulation of vascular tone, proliferation and hypertrophy of smooth muscle and angiogenesis. Since proteases are activated under pathological conditions such as hemorrhage, tissue damage, and inflammation, PARs are suggested to play a critical role in the development of functional and structural abnormality in the vascular lesion. Understanding the functional role of PARs in the vascular system can thus help in the development of new strategies for the prevention and therapy of vascular diseases.
The aim of this study was to clarify the mechanism of an inhibitory effect of nipradilol on cultured rat vascular smooth muscle cell (VSMC) growth. After being starved, cultured VSMCs were stimulated by 5% fetal bovine serum with various concentrations of nipradilol. Nipradilol dose-dependently decreased the values of [3H]-thymidine incorporation, cell numbers and total cellular protein content, and the levels of phosphorylated extracellular signal-regulated protein kinase 1/2 and p38. It also suppressed the level of proliferative cell nuclear antigen in a dose-dependent manner. In contrast, nipradilol did not change the level of the phosphorylated value of c-jun NH2-terminal protein kinase or cytoplasmic histone-associated DNA fragments in VSMCs. These results indicate that nipradilol suppresses cell growth without apoptosis in rat VSMCs, suggesting that it could be effective for preventing the progression of restenosis after angioplasty.
Plasma adiponectin levels are reduced in middle-aged obesity and in patients with type 2 diabetes and coronary artery disease. The purpose of this study was to investigate the effects of early-aged obesity on plasma adiponectin level. Twenty-six male college students (19.2 ± 1.1 years, obese group: n = 15, [body mass index > 25, percent body fat > 25%], non-obese group: n = 11) participated in the present study. We measured anthropometric parameters and plasma adiponectin and leptin level. Plasma adiponectin levels in the obese group were significantly lower than those in the non-obese group (obese: 4.7 ± 2.0 μg/ml, non-obese: 6.8 ± 2.2 μg/ml, p < 0.05). On the other hand, plasma leptin levels in the obese group were significantly higher than those in the non-obese group (obese: 8.4 ± 3.2 ng/ml, non-obese: 2.6 ± 2.1 ng/ml, p < 0.001). Plasma adiponectin levels were significantly correlated with body weight (r = − 0.415, p < 0.05) and percent body fat (r = − 0.412, p < 0.05). Stepwise multiple regression analysis revealed that percent body fat was a significant independent predictor of plasma adiponectin level (r = 0.406, p < 0.05). These results show that obesity is associated with reduced plasma adiponectin even in young subjects.
To understand the role of the cell cycle regulatory protein in the control of smooth muscle cell (SMC) proliferation, we tested the overexpression of p21Waf1, a cyclin-dependent kinase inhibitor, in human normal (MS9) and immortalized SMCs (ISS10) transfected with ori-minus simian virus 40 DNA, using an adenovirus-mediated system. In MS9, overexpression of p21Waf1 resulted in the inhibition of cell cycle progression at the G1/S boundary without apoptosis. On the other hand, in ISS10, overexpression of p21Waf1 induced marked apoptosis. In these cells, immunohistochemistry revealed that overexpressed p21Waf1 was localized in the nucleus. No differential expression pattern of either p53 or SV40T was observed in p21Waf1- and control gene (β-galactosidase)-infected cells. Old-passaged ISS10 cells eventually showed growth arrest and a senescent-like phenotype. Immunohistochemistry revealed that p21Waf1 was localized in the cytoplasm of the early-passaged cells, but was found in the nucleus of the old-passaged cells. Our data suggested that nuclear accumulation of p21Waf1 plays a role in the cell death of immortalized SMC, which carries dysfunction of the cell cycle regulatory proteins such as p53. This culture model may be useful for studying the process of SMC proliferation, cell death, senescence, and cell cycle regulation.
The aim of the present study was to investigate the independent association of the intimal-medial thickness of carotid and femoral arteries (CA-IMT and FA-IMT), a marker of atheroscelosis, with insulin resistance in type 2 diabetic patients. We evaluated CA-IMT and FA-IMT by high-resolution ultrasonography and insulin resistance determined by euglycemic hyperinsulinemic clamp in 119 type 2 diabetic subjects, 71 males and 48 females (age, 54 ± 12 (SD) years). In simple regression analyses, CA-IMT and FA-IMT were significantly inversely correlated with insulin sensitivity index (CA-IMT, r = − 0.225, p = 0.010; FA-IMT, r = − 0.186, p = 0.043, respectively). Multiple regression analysis was performed with the logarithm of CA-IMT or FA-IMT as a dependent variable and insulin sensitivity index as an independent variable along with known clinical risk factors. Insulin sensitivity index exhibited a significant independent contribution to log (CA-IMT) (β = − 0.204, p = 0.033) and to log (FA-IMT) (β = − 0.237, p = 0.010) in these models (CA-IMT, R2 = 0.347, p < 0.0001; FA-IMT, R2 = 0.398, p < 0.0001, respectively). In conclusion, insulin resistance is associated with both CA-IMT and FA-IMT in type 2 diabetic patients, suggesting that it is an independent risk factor for the development of atherosclerosis in type 2 diabetes.
Objective: Patients with type 2 diabetes mellitus are at an increased risk of atherosclerosis including peripheral arterial disease (PAD). The purpose of this study was to examine the possible alteration in pulse wave velocity (PWV) in lower-limb arteries among diabetic patients with PAD. Methods: We measured brachial-ankle PWV (baPWV) using an automatic device in 101 healthy control subjects and 102 type 2 diabetic patients including those with PAD. Results: Diabetic patients without PAD showed a higher baPWV than the healthy control subjects. There was no significant difference in baPWV between the right and left legs in these groups. In contrast, among diabetic patients with PAD, baPWV was significantly lower in the affected legs than in the non-affected legs, and the reduction in baPWV was greater in those with lower ankle-brachial pressure index (ABI). In the patients with PAD who received percutaneous transluminal angioplasty, both baPWV and ABI were increased following successful vessel dilatation. Conclusions: These results suggest that baPWV is increased in diabetic patients, whereas it is decreased in the affected legs in diabetic patients with PAD. Widening of the right-left difference in baPWV may be a novel marker of PAD.
Elevated resting heart rate (HR) is associated with hypertension in addition to or similar to increased incidence of cardiovascular morbidity and mortality. Subjects with high HR exhibit the characteristic features of insulin resistance syndrome. Sympathetic overactivity underlies this clinical condition. However, the true mechanism of high HR is unclear. We examined the relation between resting HR and age, gender, traditional coronary risk factors, and white blood cell (WBC) count in urban Japanese. The study population comprised 2, 736 people aged 40, 50, and 60 years old. Multiple regression analysis of the total population showed that gender (p < 0.001), systolic and diastolic blood pressure (SBP, DBP; p < 0.001), serum triglycerides (TG; p < 0.001), fasting plasma glucose (FPG; p < 0.001) and WBC count (p < 0.001) had significant correlations with HR in the total population. Exercise was negatively correlated with HR (p < 0.001). In the age-adjusted profiles, gender (p < 0.001), SBP (p < 0.001), FPG (p < 0.001, p < 0.01 at age 40 years) and WBC count (p < 0.001) showed a significant correlation with HR among all three age groups. A negative association between HDL cholesterol (HDLc) and HR was seen at age 60 years (p < 0.01). A negative correlation between exercise and HR was seen at age 40 years (p < 0.001) and age 50 years (p < 0.01). It is suggested that the WBC count is one of the important determinants of resting HR regardless of age. Further studies are necessary to clarify the link between HR, coronary risk factors, and chronic infections.