Thrombocytopenia and platelet abnormalities in high-density lipoprotein receptor-deficient mice.

OBJECTIVE: High-density lipoprotein (HDL) receptor, scavenger receptor class B, type I (SR-BI), mediated cellular uptake of lipoprotein cholesterol controls HDL structure and plasma HDL and biliary cholesterol levels. In SR-BI knockout (KO) mice, an unusually high plasma unesterified-to-total cholesterol ratio (UC:TC) and abnormally large HDL particles apparently contribute to pathology, including female infertility, susceptibility to atherosclerosis and coronary heart disease, and anemia. Here we examined the influence of SR-BI deficiency on platelets. METHODS AND RESULTS: The high plasma UC:TC ratio in SR-BI KO mice was correlated with platelet abnormalities, including high cholesterol content, abnormal morphologies, high clearance rates, and thrombocytopenia. One day after platelets from wild-type mice were infused into SR-BI KO mice, they exhibited abnormally high cholesterol content and clearance rates similar to those of endogenous platelets. Platelets from SR-BI KO mice exhibited in vitro a blunted aggregation response to the agonist ADP but a normal response to PAR4. CONCLUSIONS: In SR-BI KO mice abnormal circulating lipoproteins, particularly their high UC:TC ratio-rather than the absence of SR-BI in platelets themselves-induce defects in platelet structure and clearance, together with a mild defect in function.

Decreased plasma fibronectin leads to delayed thrombus growth in injured arterioles.

OBJECTIVE: Plasma fibronectin (FN) is decreased in several clinical conditions. We were interested to study the thrombotic and hemostatic consequences of the decrease in plasma FN (pFN), the role of FN splice variants in thrombosis, and to examine whether pFN incorporates into thrombi in vivo. METHODS AND RESULTS: We compared the thrombotic response to a vessel injury in FN heterozygous (FN+/-) mice and corresponding FN+/+ mice. Although normal thrombosis in venules was observed, a decrease to half in the pFN concentration in FN+/- mice caused a delay in the appearance of thrombi in arterioles and consequently a delay in their occlusion. We were able to rescue the thrombotic defect in the FN+/- mice by infusion of rat pFN. Additionally, we could show intense incorporation of fluorescent pFN-coated microspheres into the developing thrombi. Moreover, we found that mice expressing FN without the EIIIA or EIIIB domains specific to cellular FN including platelet FN had no thrombotic defect. CONCLUSIONS: Mice heterozygous for FN have a striking defect in thrombus initiation and growth in arterioles attributable to the decrease of pFN. Our study is an example of haploid insufficiency for FN, and it emphasizes the fundamental role of this plasma protein in thrombosis in the arterial system.

Protein remodeling of the heart ventricles in hereditary hypertriglyceridemic rat: effect of ACE-inhibition.

The aim of this study was to determine whether protein remodeling of the heart ventricles and remodeling of the aorta were present in hereditary hypertriglyceridemic (hHTG) rats and whether treatment with the angiotensin-converting enzyme inhibitor, captopril could prevent these alterations. Three groups of rats were investigated in a four week experiment control Wistar /C/rats, hHTg rats, hHTg rats given captopril (100 mg/kg/day) (hHTg + CAP). In the hHTg group, the increased systolic blood pressure (SBP) was associated with hypertrophy of the LV and RV. Protein profile analysis revealed an enhancement of metabolic protein concentration in both ventricles. The concentration of total collagenous proteins was not changed in either ventricles. However, alterations in composition of cardiac collagen were detected, characterized by higher concentration of hydroxyproline in pepsin-insoluble fraction and lower concentration of hydroxyproline in pepsin soluble faction in the LV. Hypertrophy of aorta, associated with the reduction of nitric oxide dependent relaxation, was also present in hHTG rats. Captopril normalized SBP, reduced left ventricular hypertrophy (LVH), diminished metabolic protein concentration in both ventricles, and improved NO-dependent relaxation of the aorta. Furthermore, captopril partially reversed alterations in hydroxyproline concentration in soluble and insoluble collagenous fractions of the LV. We conclude that hypertrophy of both ventricles and the aorta are present in hHTG rats, along with protein remodeling of both ventricles. Captopril partially prevented left ventricular hypertrophy development and protein remodeling of the myocardium.

Rilmenidine prevents blood pressure increase in rats with compromised nitric oxide production.

AIM: To search tools of high blood pressure in the model of nitric oxide (NO)-defective hypertension, and the study focused on the effect of rilmenidine, agonist of imidazoline receptors, which was suggested to modulate central sympathetic outflow. METHODS: Three experimental groups, each consisting of 7 rats, were used: (I) rats with inhibition of NO synthase (NOS) by N(G)-nitro-L-arginine methyl ester (L-NAME) 40 mg.kg(-1).d(-1) for 4 weeks in drinking water, (II) rats with inhibited NOS as in group I , plus agonist of imidazoline receptors rilmenidine 3 mg.kg(-1).d(-1) for 4 weeks by gavage, and (III) control rats. Systolic blood pressure was measured weekly noninvasively. At the end of experiment aortic ring isometric tension was followed, NOS expression (aorta, left ventricle), and NOS activity (left ventricle and brain) were determined. RESULTS: In the group I systolic blood pressure increased significantly, aortic ring relaxation to acetylcholine was significantly attenuated. Rilmenidine administered simultaneously with L-NAME (group II) prevented the increase of blood pressure which did not differ significantly from control values; aortic ring relaxation to acetylcholine did not differ from control. No change in NOS expression (aorta and left ventricle) was found in groups I and II. Significant decline in NOS activity (left ventricle and brain) was found in groups I and II. CONCLUSION: Rilmenidine has a remarkable role in NO-defective hypertension, possibly by inhibiting central sympathetic outflow and by affecting receptors in vascular smooth muscle also. The prime cause of hypertension in this experimental model--the compromised production of NO due to inhibition of NOS--was not affected by rilmenidine.

Effect of simvastatin on remodeling of the left ventricle and aorta in L-NAME-induced hypertension.

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been shown to prevent or reverse hypertrophy of the LV in several models of left ventricular hypertrophy. The aim of the present study was to determine whether treatment with simvastatin can prevent hypertension, reduction of tissue nitric oxide synthase activity and left ventricular (LV) remodeling in NG-nitro-L-arginine methyl ester(L-NAME)-induced hypertension. Four groups of rats were investigated: control, simvastatin (10 mg/kg), L-NAME (40 mg/kg) and L-NAME + simvastatin (in corresponding doses). Animals were sacrificed and studied after 6 weeks of treatment. The decrease of NO-synthase activity in the LV, kidney and brain was associated with hypertension, LV hypertrophy and fibrosis development and remodeling of the aorta in the L-NAME group. Simvastatin attenuated the inhibition of NO-synthase activity in kidney and brain, partly prevented hypertension development and reduced the concentration of coenzyme Q in the LV. Nevertheless, myocardial hypertrophy, fibrosis and enhancement of DNA concentration in the LV, and remodeling of the aorta were not prevented by simultaneous simvastatin treatment in the L-NAME treated animals. We conclude that the HMG-CoA reductase inhibitor simvastatin improved nitric oxide production and partially prevented hypertension development, without preventing remodeling of the left ventricle and aorta in NO-deficient hypertension.