Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies in man and human apolipoprotein A-I transgenic animals emphasize the significance of apolipoprotein A-I and high density lipoprotein in antiatherogenesis. Several drugs and other compounds, e.g. phenobarbital, gemfibrozil, fenofibrate, prednisone, estrogen and alcohol, induce apolipoprotein A-I synthesis. They commonly produce serum lipoprotein patterns typical of a low risk of coronary heart disease, and many of them have been found to prevent atherogenesis, reduce coronary heart disease mortality and increase survival. These compounds act against atherosclerosis by using one or several mechanisms that include overexpression of the apolipoprotein A-I gene with an increase in serum apolipoprotein A-I and high density lipoprotein and promotion of reverse cholesterol transport, upregulation of the low density lipoprotein receptor gene with a decrease in serum apolipoprotein B and low density lipoprotein, maintenance of endothelial cell function and protection against thrombosis. They have been found to raise high density lipoprotein cholesterol and apolipoprotein A-I together with a decrease in cholesterol ester transfer protein activity, and to induce hepatic cholesterol 7 alpha-hydroxylase and cholesterol and bile acid elimination from the body. By raising the activities of apolipoprotein A-I/high density lipoprotein-associated paraoxonase and other antioxidative enzymes, the inducers have the capacity to prevent atherogenesis in arterial walls through inhibition of the oxidative modification of low density lipoprotein. Other antiatherogenic vascular actions of high density lipoprotein include interference with low density lipoprotein aggregation and uptake by endothelial cells, and competition with low density lipoprotein for endothelial-localized low density lipoprotein receptors. Apolipoprotein A-I/high density lipoprotein beneficially enhances fibrinolysis, decreases platelet aggregation, increases prostacyclin production and stabilization and prevents atherogenic immune and inflammatory responses. This gene activation or microsomal induction can prevent atherosclerosis and is a basis for tailoring effective new agents and optimal non-invasive therapy against atherosclerotic vascular disease to promote health and enhance longevity.
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PMID:Gene activation, apolipoprotein A-I/high density lipoprotein, atherosclerosis prevention and longevity. 929 1

The very low density lipoprotein receptor (VLDLR) is a multifunctional apolipoprotein (apo) E receptor that shares a common structural feature as well as some ligand specificity to apo E with members of the low density lipoprotein receptor gene family. We have isolated and characterized the mouse VLDLR gene. The mouse VLDLR gene contains 19 exons spanning approximately 50 kb. The exon-intron organization of the gene is completely conserved between mouse and human. Since the 5'-flanking region of the mouse VLDLR gene contains two copies of a sterol regulatory element-1 like sequence (SRE-1), we next studied regulation of the VLDLR mRNA expression in heart, skeletal muscle and adipose tissue in C57BL/6, LDLR-/-, apo E-/- and LDLR-/-apo E-/- mice fed normal chow or atherogenic diet. The VLDLR mRNA expression was down-regulated 3-fold by feeding atherogenic diet in heart and skeletal muscle only in LDLR-/- mice. In contrast, VLDLR mRNA expression was up-regulated by atherogenic diet in adipose tissue in all animal models except double knockout mice. These results suggest that SRE-1 may be functional and VLDLR plays a role in cholesterol homeostasis in heart and skeletal muscle when LDLR is absent and that apo E is required for this modulation. Developmental regulation of the VLDLR mRNA expression was also tissue-specific. VLDLR mRNA expression in heart displayed significant up and down regulation during development. Maximal level was detected on post-natal day 3. However, the VLDLR mRNA levels in skeletal muscle remained relatively constant except a slight dip on post-natal day 7. In kidney and brain, VLDLR mRNA also peaked on post-natal day 3 but remained relatively constant thereafter. In liver, VLDLR mRNA expression was very low; it was barely detectable at day 19 of gestation and was decreased further thereafter. In adipose tissue, the VLDLR mRNA level showed an increase on post-natal day 13, went down again during weaning and then continued to increase afterwards. This developmental pattern as well as dietary regulation in adipose tissue supports the notion that VLDLR plays a role in lipid accumulation in this tissue. Although the primary role of VLDLR in heart, muscle and adipose tissue is likely in lipid metabolism, developmental pattern of this receptor in other tissues suggests that VLDLR has functions that are unrelated to lipid metabolism.
Atherosclerosis 1999 Aug
PMID:Mouse very low-density lipoprotein receptor (VLDLR): gene structure, tissue-specific expression and dietary and developmental regulation. 1048 49

Mutations in the low density lipoprotein receptor gene (LDLR) cause familial hypercholesterolaemia (FH). The FH website (http://www.ucl. ac.uk/fh) has been updated to provide various functions enabling the analysis of the large number of LDLR mutations. To date, 683 LDLR mutations have been reported; of these 58.9% are missense mutations, 21.1% minor rearrangements, 13.5% major rearrangements and 6.6% splice site mutations. Of the 402 missense mutations, only 11.4% occurred at CpG sites. The majority of mutations were found in two functional domains, the ligand binding domain (42%) and the epidermal growth factor (EGF) precursor-like domain (47%). This report describes new features of the FH website and assesses the spectrum of mutations reported to date.
Atherosclerosis 2001 Jan
PMID:Low-density lipoprotein receptor gene (LDLR) world-wide website in familial hypercholesterolaemia: update, new features and mutation analysis. 1113 6

The clinical phenotype of heterozygous familial hypercholesterolemia (FH) is characterized by increased plasma levels of total cholesterol and low density lipoprotein cholesterol, tendinous xanthomata, and premature symptoms of coronary heart disease. It is inherited as an autosomal dominant disorder with homozygotes having a more severe phenotype than do heterozygotes. FH can result from mutations in the low density lipoprotein receptor gene (LDLR), the apolipoprotein B-100 gene (APOB), and the recently identified proprotein convertase subtilisin/kexin type 9 gene (PCSK9). To date, over 700 variants have been identified in the LDLR gene. With the exception of a small number of founder populations where one or two mutations predominate, most geographically based surveys of FH subjects show a large number of mutations segregating in a given population. Studies of the prevalence of FH would be improved by the use of a consistent and uniformly applied clinical definition. Because FH responds well to drug treatment, early diagnosis to reduce atherosclerosis risk is beneficial. Cascade testing of FH family members is cost effective and merits further research. For screening to be successful, public health and general practitioners need to be aware of the signs and diagnosis of FH and the benefits of early treatment.
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PMID:Genetic causes of monogenic heterozygous familial hypercholesterolemia: a HuGE prevalence review. 1532 37

Atherosclerosis is a leading underlying factor in cardiovascular disease and stroke, important causes of morbidity and mortality across the globe. Abundant epidemiological studies demonstrate that high levels of high density lipoprotein (HDL) are associated with reduced risk of atherosclerosis and preclinical, animal model studies demonstrate that this association is causative. Understanding the molecular mechanisms underlying the protective effects of HDL will allow more strategic approaches to development of HDL based therapeutics. Recent evidence suggests that an important aspect of the ability of HDL to protect against atherosclerosis is its ability to trigger signaling responses in a variety of target cells including endothelial cells and macrophages in the vessel wall. These signaling responses require the HDL receptor, scavenger receptor class B type 1 (SR-B1), an adaptor protein (PDZK1) that binds to the cytosolic C terminus of SR-B1, Akt1 activation and (at least in endothelial cells) activation of endothelial NO synthase (eNOS). Mouse models of atherosclerosis, exemplified by apolipoprotein E or low density lipoprotein receptor gene inactivated mice (apoE or LDLR KO) develop atherosclerosis in their aortas but appear generally resistant to coronary artery atherosclerosis. On the other hand, inactivation of each of the components of HDL signaling (above) in either apoE or LDLR KO mice renders them susceptible to extensive coronary artery atherosclerosis suggesting that HDL signaling may play an important role in protection against coronary artery disease.
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PMID:HDL signaling and protection against coronary artery atherosclerosis in mice. 2664 35

Cardiovascular disease is the leading cause of morbidity and mortality globally, as estimated by the World Health Organization, where in 2016, 15.2 million deaths were attributed to ischemic heart disease and stroke. It is therefore essential to try to reduce the incidence of Cardiovascular disease by controlling modifiable risk factors. One such major modifiable risk factor is cholesterol, which influences the pathogenesis and progression of atherosclerosis. Statins are often prescribed to lower blood levels of low density lipoprotein cholesterol, thereby reducing the risk of Cardiovascular disease by approximately 25-35%. However, there is an increasing number of patients (in particular those with intolerance to statin therapy and those with familial hypercholesterolemia) for whom statin therapy alone is not enough to control low density lipoprotein cholesterol. In this review, the regulation of cholesterol metabolism will be discussed with an emphasis on novel cholesterol lowering drugs used in clinical trials. These second-generation drugs, monoclonal antibodies against the low density lipoprotein receptor gene known as proprotein convertase subtilisin/kexin type 9 inhibitors, are expected to be prescribed to patients who are intolerant to statins, as well as in conjunction with statins. Future perspectives of the clinical use of these drugs is also discussed.
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PMID:A short review of proprotein convertase subtilisin/kexin type 9 inhibitors. 3118 90