Cardiovascular functional phenotypes and pharmacological responses in apolipoprotein E deficient mice.
This is an overview of recent findings, mainly from our laboratory, describing the cardiovascular functional phenotypes and pharmacological responses in mice genetically deficient in apolipoprotein E (apoE-KO). ApoE-KO mice are hyperlipidemic and spontaneously develop atherosclerosis. We have detected several new cardiovascular functional phenotypes in apoE-KO mice: hyperglycemia, age-dependent aortic stiffening, cardiac hypertrophy and increased cardiac output. Angiotensin II (Ang II) promoted vascular inflammation and atherosclerosis, increased vascular stiffness, and induced abdominal aortic aneurysm (AAA) in apoE-KO mice, in which activation of NF-kappaB mediated pro-inflammatory genes plays an important role. Inhibition of nitric oxide (NO) synthesis with N(omega)-nitro-L-arginine methyl ester (L-NAME) significantly inhibited NO-mediated vascular responses and accelerated atherosclerosis in apoE-KO mice, supporting a protective role of NO against atherosclerosis. Estrogen attenuated atherosclerosis in apoE-KO mice, even in those with atherosclerosis being accelerated by Ang II, hyperglycemia, or L-NAME, demonstrating an anti-atherosclerotic effect of estrogen. Simvastatin paradoxically increased lipid and atherosclerosis in apoE-KO mice, but it decreased lipid and atherosclerosis in LDLR-KO mice, indicating that anti-atherosclerotic effect of simvastatin requires the presence of an intact apoE.
Wang
Yi-Xin
YX
Department of Pharmacology, Berlex Biosciences, P.O. Box 4099, 2600 Hilltop Drive, Richmond, CA 94804-0099, USA. jim_wang@berlex.com
D000804:Angiotensin II / Q000502:physiology; D000818:Animals; D001018:Aortic Diseases / Q000235:genetics* / Q000503:physiopathology; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics*; D001161:Arteriosclerosis / Q000235:genetics / Q000503:physiopathology; D016534:Cardiac Output, High / Q000235:genetics / Q000503:physiopathology; D006332:Cardiomegaly / Q000235:genetics* / Q000503:physiopathology; D002319:Cardiovascular System / Q000187:drug effects / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000502:physiology; D006937:Hypercholesterolemia / Q000503:physiopathology; D006943:Hyperglycemia / Q000235:genetics* / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D010641:Phenotype; D019821:Simvastatin / Q000494:pharmacology
D001057:Apolipoproteins E; D004791:Enzyme Inhibitors; D000804:Angiotensin II; D004958:Estradiol; D019821:Simvastatin; D019331:NG-Nitroarginine Methyl Ester