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Novel Molecules Targeting Dyslipidemia and Atherosclerosis

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Abstract:

Atherosclerotic cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide. Dyslipidemia is one of the main risk factors leading to atherosclerosis. Moreover, there is evidence for a role of oxidation in linking lipids and inflammation to development and progression of atherosclerosis. Current therapeutic approaches with lipid-lowering agents, such as statins, fail to protect more than half of patients from cardiovascular events. Therefore, there is a need for additional and alternative treatment options. There are several novel molecules undergoing preclinical or clinical development for the treatment of dyslipidemia or against distinct pathways which contribute to the development of atherosclerosis. Novel squalene synthase inhibitors with significant cholesterollowering and antiatherosclerotic properties are under development. Targeting the production of apolipoprotein B-100 with an antisense oligonucleotide is another interesting approach for lowering low density lipoprotein(LDL)-cholesterol levels. Raising high density lipoprotein( HDL)-cholesterol levels or improving its antiatherosclerotic properties constitute additional attractive targets for protection against CVD. Such compounds include the cholesteryl ester transfer protein inhibitors, HDL-derived proteins, and mimetic peptides/ lipids. Direct targeting of atherosclerosis remains a challenge. Molecules against oxidation and/or inflammation could be beneficial in reducing atherosclerosis. Other targets involved in distinct pathways of atherosclerosis include the lipoprotein-associated phospholipase A2, 5-lipoxygenase-activating protein, acyl-CoA:cholesterol acyltransferase, chemokine receptors, and protein kinases. In conclusion, there are several promising novel therapeutic approaches for dyslipidemia and atherosclerosis under development which are expected to be of great benefit for patients at risk of CVD.

Keywords: HDL-modifying agents; Novel molecules; anti-atherosclerotic agents; antisense oligonucleotides; atherosclerosis; cholesterol-lowering agents; dyslipidemia; squalene synthase inhibitors

Document Type: Research Article

DOI: https://doi.org/10.2174/092986708783955482

Affiliations: Laboratory of Pharmacology, Medical School, Democritus University of Thrace, Alexandroupolis 68100, Greece.

Publication date: 2008-04-01

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