In Search for Genes Related to Atherosclerosis and Dyslipidemia Using Animal Models

Abstract

Atherosclerosis is a multifactorial chronic disease that affects large arteries and may lead to fatal consequences. According to current understanding, inflammation and lipid accumulation are the two key mechanisms of atherosclerosis development. Animal models based on genetically modified mice have been developed to investigate these aspects. One such model is low-density lipoprotein (LDL) receptor knockout (KO) mice (ldlr −/− ), which are characterized by a moderate increase of plasma LDL cholesterol levels. Another widely used genetically modified mouse strain is apolipoprotein-E KO mice (apoE −/− ) that lacks the primary lipoprotein required for the uptake of lipoproteins through the hepatic receptors, leading to even greater plasma cholesterol increase than in ldlr −/− mice. These and other animal models allowed for conducting genetic studies, such as genome-wide association studies, microarrays, and genotyping methods, which helped identifying more than 100 mutations that contribute to atherosclerosis development. However, translation of the results obtained in animal models for human situations was slow and challenging. At the same time, genetic studies conducted in humans were limited by low sample sizes and high heterogeneity in predictive subclinical phenotypes. In this review, we summarize the current knowledge on the use of KO mice for identification of genes implicated in atherosclerosis and provide a list of genes involved in atherosclerosis-associated inflammatory pathways and their brief characteristics. Moreover, we discuss the approaches for candidate gene search in animals and humans and discuss the progress made in the field of epigenetic studies that appear to be promising for identification of novel biomarkers and therapeutic targets.challenge is the lack of effective treatment approaches, which is the consequence of our incomplete understanding of the processes that underlie the pathogenesis. Genetic base is one of the most important features that are involved in the disease development.Currently, the most widely used anti-atherosclerosis drugs are statins [3]. The aim of statin therapy is reducing the blood level of low-density lipoprotein (LDL) cholesterol, which is a well-known pro-atherogenic agent. It was demonstrated that statin therapy reduces the risk of cardiovascular events by approximately one third [4]. However, statin therapy alone cannot be regarded as effective treatment of atherosclerosis. Increasing the plasma levels of high-density lipoprotein (HDL), which has anti-atherogenic properties, is another promising approach. Accumulating evidence shows that high levels of HDL cholesterol can inhibit atherosclerosis progression. To date, several therapeutic agents that increase HDL levels are known, including niacin, fibrates, and statins. Among the recently developed medications are apoA-I-phospholipid complexes, human apoA-I and apoA-I-mimetic peptides, and inhibitors of cholesterol ester transfer protein, which have reached the level of clinical trials. However, the inhibitor ...

Facts about Fats: New Insights into the Role of Lipids in Metabolism, Disease and Therapy

“…The exact etiopathogenesis of atherosclerosis is not fully elucidated, however, several risk factors have been identified, such as high blood pressure, hypercholesterolemia, obesity and diabetes. In their review article, Poznyak and colleagues provided up-to-date information about the use of knockout mice as experimental models to investigate genes involved in atherosclerosis and dyslipidemia [10]. In addition, Poznyak et al discuss the current knowledge concerning the mechanisms by which diabetes mellitus promotes the atherogenic process, and summarize the physiopathological hallmarks linking atherosclerosis and diabetes mellitus, such as protein kinase signaling, oxidative stress, miRNA alterations and epigenetic changes [11].…”

Natural Killer T Cells Are Involved in Atherosclerotic Plaque Instability in Apolipoprotein-E Knockout Mice

“…We previously demonstrated that in vivo administration of αGC decreased collagen content and increased cellularity of atherosclerotic lesions in the aortic sinus from apoE knockout mice, suggesting that iNKT cells may affect the plaque instability [5]. However, the relevance of changes in the atherosclerotic lesions in the aortic sinus is rather limited because the incident plaque rupture is very rare in the aortic sinus [10,11]. In contrast, in an animal model that we employed in the present study, HFD feeding can develop advanced atherosclerotic lesions in the brachiocephalic artery from apoE knockout mice with several morphological features similar to human ruptured plaques [12,13].…”

Cardiac Mitochondria Dysfunction in Dyslipidemic Mice

“…Murine knockouts of apolipoprotein E ( Apoe−/− ) and LDL receptor ( Ldlr−/− ), as well as the hybrid knockout for both genes ( Apoe−/− Ldlr−/− ), are well-established experimental models of dyslipidemia that diligently reflect this pathology in humans [ 5 ]. It has been demonstrated that during dyslipidemia and atherosclerosis, cardiac function was attenuated as a consequence of diminished oxygen supply [ 6 ].…”