TY - JOUR
T1 - Simvastatin preserves coronary endothelial function in hypercholesterolemia in the absence of lipid lowering
AU - Wilson, Stephanie H.
AU - Simari, Robert D.
AU - Best, Patricia J.M.
AU - Peterson, Tim E.
AU - Lerman, Lilach O.
AU - Aviram, Michael
AU - Nath, Karl A.
AU - Holmes, David R.
AU - Lerman, Amir
PY - 2001
Y1 - 2001
N2 - Recent evidence suggests that some benefit from the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors may occur independent of lipid lowering. We aimed to determine the effect of simvastatin on coronary endothelial function, endothelial NO synthase (eNOS) expression and oxidative stress in experimental hypercholesterolemia (HC) in the absence of cholesterol lowering. Pigs were randomized to 3 experimental groups: Normal diet (N group), high cholesterol diet (HC group), and HC diet with simvastatin (HC+S group) for 12 weeks. Low density lipoprotein cholesterol was similarly increased in the HC and HC+S groups compared with the N group. In vitro analysis of coronary large- and small-vessel endothelium-dependent vasorelaxation was performed. The mean vasorelaxation of epicardial vessels to bradykinin was significantly attenuated in the HC group compared with the N group (32.3±1.2% versus 42.9±1.6%, respectively; P<0.0001). This attenuation was significantly reversed in the HC+S group (38.7±1.5%, P<0.005 versus HC group). The maximal vasorelaxation to substance P was significantly attenuated in the HC group compared with the N group (50.5±11.9% versus 79.3±5.3%, respectively; P<0.05). This attenuated response was normalized in the HC+S group (74.9±4.1%, P<0.05 versus HC group). The maximal arteriolar vasorelaxation to bradykinin was also significantly attenuated in the HC group compared with the N group (71.9±4.9% versus 96.8±1.34%, respectively; P<0.005). This was reversed in the HC+S group (98.4±0.6%, P<0.0001 versus HC group). Western blotting of coronary tissue homogenates for eNOS demonstrated a decrease in protein levels in the HC group compared with the N group, with normalization in the HC+S group. Elevation of plasma F2-isoprostanes and thiobarbituric acid-reactive substances, markers of oxidative stress, occurred in the HC compared with the N group. These changes were reversed in the HC+S group. In summary, simvastatin preserves endothelial function in coronary epicardial vessels and arterioles in experimental HC (in the absence of cholesterol lowering) in association with an increase in coronary eNOS levels and a decrease in oxidative stress. These alterations may play a role in the reduction in cardiac events after treatment with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors.
AB - Recent evidence suggests that some benefit from the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors may occur independent of lipid lowering. We aimed to determine the effect of simvastatin on coronary endothelial function, endothelial NO synthase (eNOS) expression and oxidative stress in experimental hypercholesterolemia (HC) in the absence of cholesterol lowering. Pigs were randomized to 3 experimental groups: Normal diet (N group), high cholesterol diet (HC group), and HC diet with simvastatin (HC+S group) for 12 weeks. Low density lipoprotein cholesterol was similarly increased in the HC and HC+S groups compared with the N group. In vitro analysis of coronary large- and small-vessel endothelium-dependent vasorelaxation was performed. The mean vasorelaxation of epicardial vessels to bradykinin was significantly attenuated in the HC group compared with the N group (32.3±1.2% versus 42.9±1.6%, respectively; P<0.0001). This attenuation was significantly reversed in the HC+S group (38.7±1.5%, P<0.005 versus HC group). The maximal vasorelaxation to substance P was significantly attenuated in the HC group compared with the N group (50.5±11.9% versus 79.3±5.3%, respectively; P<0.05). This attenuated response was normalized in the HC+S group (74.9±4.1%, P<0.05 versus HC group). The maximal arteriolar vasorelaxation to bradykinin was also significantly attenuated in the HC group compared with the N group (71.9±4.9% versus 96.8±1.34%, respectively; P<0.005). This was reversed in the HC+S group (98.4±0.6%, P<0.0001 versus HC group). Western blotting of coronary tissue homogenates for eNOS demonstrated a decrease in protein levels in the HC group compared with the N group, with normalization in the HC+S group. Elevation of plasma F2-isoprostanes and thiobarbituric acid-reactive substances, markers of oxidative stress, occurred in the HC compared with the N group. These changes were reversed in the HC+S group. In summary, simvastatin preserves endothelial function in coronary epicardial vessels and arterioles in experimental HC (in the absence of cholesterol lowering) in association with an increase in coronary eNOS levels and a decrease in oxidative stress. These alterations may play a role in the reduction in cardiac events after treatment with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors.
KW - Endothelial NO synthase
KW - Hypercholesterolemia
KW - Nitric oxide
KW - Vasorelaxation
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U2 - 10.1161/01.ATV.21.1.122
DO - 10.1161/01.ATV.21.1.122
M3 - Article
C2 - 11145943
AN - SCOPUS:0035162842
SN - 1079-5642
VL - 21
SP - 122
EP - 128
JO - Arteriosclerosis, thrombosis, and vascular biology
JF - Arteriosclerosis, thrombosis, and vascular biology
IS - 1
ER -