Anti-atherosclerotic effect of simvastatin depends on the presence of apolipoprotein E.

Low density lipoprotein receptor deficient (LDLR-KO) and apolipoprotein E deficient (apo E-KO) mice both develop hyperlipidemia and atherosclerosis by different mechanisms. The aim of the present study was to compare the effects of simvastatin on cholesterol levels, endothelial dysfunction, and aortic lesions in these two models of experimental atherosclerosis. Male LDLR-KO mice fed a high cholesterol (HC; 1%) diet developed atherosclerosis at 8 months of age with hypercholesterolemia. The addition of simvastatin (300 mg/kg daily) to the HC diet for 2 more months lowered total cholesterol levels by approximately 57% and reduced aortic plaque area by approximately 15% compared with the LDLR-KO mice continued on HC diet alone, P<0.05. Simvastatin treatment also improved acetylcholine (ACh)-induced endothelium-dependent vasorelaxation in isolated aortic rings, which was associated with an increase in NOS-3 expression by approximately 88% in the aorta measured by real time polymerase chain reaction (PCR), P<0.05. In contrast, in age-matched male apo E-KO mice fed a normal diet, the same treatment of simvastatin elevated serum total cholesterol by approximately 35%, increased aortic plaque area by approximately 15%, and had no effect on endothelial function. These results suggest that the therapeutic effects of simvastatin may depend on the presence of a functional apolipoprotein E.

Reduction of cardiac functional reserve and elevation of aortic stiffness in hyperlipidemic Yucatan minipigs with systemic and coronary atherosclerosis.

To test the hypothesis that cardiac functional reserve is reduced in animals with severe atherosclerosis, Yucatan minipigs were fed a high-cholesterol diet (Chol) for 8 months. Half of them was made diabetic, an additional risk factor for atherosclerosis, with streptozotocin (STZ). Another group of age-matched minipigs were fed a normal diet as controls. At the end of the treatment period, animals were instrumented for the measurement of cardiovascular hemodynamic parameters under isoflurane anesthesia. Cardiac functional reserve was measured by the magnitude of the inotropic response to isoproterenol stress. Hyperlipidemic minipigs developed severe atherosclerotic plaques in the aorta, coronary and iliac artery, accompanied by an increase in the aortic stiffness indexed by increases in pulse wave velocity and augmentation index. These vascular changes were more severe in STZ-induced insulin-dependent diabetes mellitus. The isoproterenol-induced increase in left ventricular contractility (dP/dt) and relaxation (-dP/dt) and, consequently, cardiac output were also significantly reduced in both the Chol groups with or without STZ, compared to control group. Thus, cardiac functional reserve measured by isoproterenol-stimulated responses was reduced in atherosclerotic minipigs, which was further diminished in diabetes.

A selective inducible NOS dimerization inhibitor prevents systemic, cardiac, and pulmonary hemodynamic dysfunction in endotoxemic mice.

Increased nitric oxide (NO) production by inducible NO synthase (NOS2), an obligate homodimer, is implicated in the cardiovascular sequelae of sepsis. We tested the ability of a highly selective NOS2 dimerization inhibitor (BBS-2) to prevent endotoxin-induced systemic hypotension, myocardial dysfunction, and impaired hypoxic pulmonary vasoconstriction (HPV) in mice. Mice were challenged with Escherichia coli endotoxin before treatment with BBS-2 or vehicle. Systemic blood pressure was measured before and 4 and 7 h after endotoxin challenge, and echocardiographic parameters of myocardial function were measured before and 7 h after endotoxin challenge. The pulmonary vasoconstrictor response to left mainstem bronchus occlusion, which is a measure of HPV, was studied 22 h after endotoxin challenge. BBS-2 treatment alone did not alter baseline hemodynamics. BBS-2 treatment blocked NOS2 dimerization and completely inhibited the endotoxin-induced increase of plasma nitrate and nitrite levels. Treatment with BBS-2 after endotoxin administration prevented systemic hypotension and attenuated myocardial dysfunction. BBS-2 also prevented endotoxin-induced impairment of HPV. In contrast, treatment with NG-nitro-l-arginine methyl ester, which is an inhibitor of all three NOS isoforms, prevented the systemic hypotension but further aggravated the myocardial dysfunction associated with endotoxin challenge. Treatment with BBS-2 prevented endotoxin from causing key features of cardiovascular dysfunction in endotoxemic mice. Selective inhibition of NOS2 dimerization with BBS-2, while sparing the activities of other NOS isoforms, may prove to be a useful treatment strategy in sepsis.