In this mini-review several commonly used animal models of atherosclerosis have been discussed.Among them,emphasis has been made on mice,rabbits,pigs and non-human primates.Although these animal models have played a s...In this mini-review several commonly used animal models of atherosclerosis have been discussed.Among them,emphasis has been made on mice,rabbits,pigs and non-human primates.Although these animal models have played a significant role in our understanding of induction of atherosclerotic lesions,we still lack a reliable animal model for regression of the disease.Researchers have reported several genetically modified and transgenic animal models that replicate human atherosclerosis,however each of current animal models have some limitations.Among these animal models,the apolipoprotein(apo) E-knockout(KO)mice have been used extensively because they develop spontaneous atherosclerosis.Furthermore,atherosclerotic lesions developed in this model depending on experimental design may resemble humans' stable and unstable atherosclerotic lesions.This mouse model of hypercholesterolemia and atherosclerosis has been also used to investigate the impact of oxidative stress and inflammation on atherogenesis.Low density lipoprotein(LDL)-r-KO mice are a model of human familial hypercholesterolemia.However,unlike apo E-KO mice,the LDL-r-KO mice do not develop spontaneous atherosclerosis.Both apo E-KO and LDL-r-KO mice have been employed to generate other relevant mouse models of cardiovascular disease through breeding strategies.In addition to mice,rabbits have been used extensively particularly to understand the mechanisms of cholesterol-induced atherosclerosis.The present review paper details the characteristics of animal models that are used in atherosclerosis research.展开更多
Although high density lipoprotein(HDL)-mediated reverse cholesterol transport is crucial to the prevention and reversal of atheroma, a recent meta-analysis makes evident that current pharmaceutical strategies for modu...Although high density lipoprotein(HDL)-mediated reverse cholesterol transport is crucial to the prevention and reversal of atheroma, a recent meta-analysis makes evident that current pharmaceutical strategies for modulating HDL cholesterol levels lower cardiovascular risk only to the extent that they concurrently decrease low density lipoprotein(LDL) cholesterol. This corresponds well with findings of a recent Mendelian randomization analysis, in which genetic polymorphisms associated with HDL cholesterol but no other known cardiovascular risk factors failed to predict risk for myocardial infarction. Although it is still seems appropriate to search for therapies that could improve the efficiency with which HDL particles induce reverse cholesterol transport, targeting HDL cholesterol levels per se with current measures appears to be futile. Itmay therefore be more promising to promote reverse cholesterol transport with agents that directly target foam cells. Macrophage expression of the cholesterol transport proteins adenosine triphosphate binding cassette transporter A1, adenosine triphosphate binding cassette transporter G1, and scavenger receptor class B member 1 is transcriptionally up-regulated by activated liver X receptors(LXR), whereas nuclear factor(NF)-kappa B antagonizes their expression. Taurine, which inhibits atherogenesis in rodent studies, has just been discovered to act as a weak agonist for LXRalpha. Conversely, it may be possible to oppose NF-kappa B activation in macrophages with a range of measures. Induction of heme oxygenase-1, which can be attained with phase 2 inducer phytochemicals such as lipoic acid and green tea catechins, promotes reverse cholesterol transport in macrophages and inhibits atherogenesis in rodents, likely due to, in large part, NF-kappa B antagonism. Inhibition of macrophage nicotinamide adenine dinucleotide phosphate(NADPH) oxidase activity with the spirulina-derived bilirubin-mimetic phycocyanobilin may also oppose NF-kappa B activation, and salicylic acid similarly should be useful for this purpose. The 5' adenosine monophosphate-activated protein kinase activator berberine promotes macrophage reverse cholesterol transport in cell culture; metformin probably shares this property. Many of these measures could also be expected to promote plaque stability by suppressing foam cell production of inflammatory cytokines and matrix metalloproteinases, and to reduce intimal monocyte infiltration by anti-inflammatory effects on vascular endothelium. Direct targeting of foam cells with agents such as phase 2 inducers, spirulina, salicylate, taurine, and berberine or metformin, may hence have considerable potential for preventing and reversing atheroma, and for preventing the plaque rupture that triggers vascular thrombosis.展开更多
基金supported by Natural Sciences and Engineering Research Council of Canada
文摘In this mini-review several commonly used animal models of atherosclerosis have been discussed.Among them,emphasis has been made on mice,rabbits,pigs and non-human primates.Although these animal models have played a significant role in our understanding of induction of atherosclerotic lesions,we still lack a reliable animal model for regression of the disease.Researchers have reported several genetically modified and transgenic animal models that replicate human atherosclerosis,however each of current animal models have some limitations.Among these animal models,the apolipoprotein(apo) E-knockout(KO)mice have been used extensively because they develop spontaneous atherosclerosis.Furthermore,atherosclerotic lesions developed in this model depending on experimental design may resemble humans' stable and unstable atherosclerotic lesions.This mouse model of hypercholesterolemia and atherosclerosis has been also used to investigate the impact of oxidative stress and inflammation on atherogenesis.Low density lipoprotein(LDL)-r-KO mice are a model of human familial hypercholesterolemia.However,unlike apo E-KO mice,the LDL-r-KO mice do not develop spontaneous atherosclerosis.Both apo E-KO and LDL-r-KO mice have been employed to generate other relevant mouse models of cardiovascular disease through breeding strategies.In addition to mice,rabbits have been used extensively particularly to understand the mechanisms of cholesterol-induced atherosclerosis.The present review paper details the characteristics of animal models that are used in atherosclerosis research.
文摘Although high density lipoprotein(HDL)-mediated reverse cholesterol transport is crucial to the prevention and reversal of atheroma, a recent meta-analysis makes evident that current pharmaceutical strategies for modulating HDL cholesterol levels lower cardiovascular risk only to the extent that they concurrently decrease low density lipoprotein(LDL) cholesterol. This corresponds well with findings of a recent Mendelian randomization analysis, in which genetic polymorphisms associated with HDL cholesterol but no other known cardiovascular risk factors failed to predict risk for myocardial infarction. Although it is still seems appropriate to search for therapies that could improve the efficiency with which HDL particles induce reverse cholesterol transport, targeting HDL cholesterol levels per se with current measures appears to be futile. Itmay therefore be more promising to promote reverse cholesterol transport with agents that directly target foam cells. Macrophage expression of the cholesterol transport proteins adenosine triphosphate binding cassette transporter A1, adenosine triphosphate binding cassette transporter G1, and scavenger receptor class B member 1 is transcriptionally up-regulated by activated liver X receptors(LXR), whereas nuclear factor(NF)-kappa B antagonizes their expression. Taurine, which inhibits atherogenesis in rodent studies, has just been discovered to act as a weak agonist for LXRalpha. Conversely, it may be possible to oppose NF-kappa B activation in macrophages with a range of measures. Induction of heme oxygenase-1, which can be attained with phase 2 inducer phytochemicals such as lipoic acid and green tea catechins, promotes reverse cholesterol transport in macrophages and inhibits atherogenesis in rodents, likely due to, in large part, NF-kappa B antagonism. Inhibition of macrophage nicotinamide adenine dinucleotide phosphate(NADPH) oxidase activity with the spirulina-derived bilirubin-mimetic phycocyanobilin may also oppose NF-kappa B activation, and salicylic acid similarly should be useful for this purpose. The 5' adenosine monophosphate-activated protein kinase activator berberine promotes macrophage reverse cholesterol transport in cell culture; metformin probably shares this property. Many of these measures could also be expected to promote plaque stability by suppressing foam cell production of inflammatory cytokines and matrix metalloproteinases, and to reduce intimal monocyte infiltration by anti-inflammatory effects on vascular endothelium. Direct targeting of foam cells with agents such as phase 2 inducers, spirulina, salicylate, taurine, and berberine or metformin, may hence have considerable potential for preventing and reversing atheroma, and for preventing the plaque rupture that triggers vascular thrombosis.
