Targeting the Mevalonate Cascade as a New Therapeutic Approach in Heart Disease, Cancer and Pulmonary Disease

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dc.contributor.authorYeganeh, Behzad
dc.contributor.authorWiechec, Emmilia
dc.contributor.authorAnde, Sudharsana
dc.contributor.authorSharma, Pawan
dc.contributor.authorMoghadam, Adel Rezaei
dc.contributor.authorPost, Martin
dc.contributor.authorFreed, Darren H.
dc.contributor.authorHashemi, Mohammad
dc.contributor.authorShojaei, Shahla
dc.contributor.authorZeki, Amir A.
dc.contributor.authorGhavami, Saeid
dc.date.accessioned2014-03-07T17:54:49Z
dc.date.available2014-03-07T17:54:49Z
dc.date.issued2014-02-26
dc.description.abstractThe cholesterol biosynthesis pathway, also known as the mevalonate (MVA) pathway, is an essential cellular pathway that is involved in diverse cell functions. The enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMGCR) is the rate-limiting step in cholesterol biosynthesis and catalyzes the conversion of HMG-CoA to MVA. Given its role in cholesterol and isoprenoid biosynthesis, the regulation of HMGCR has been intensely investigated. Because all cells require a steady supply of MVA, both the sterol (i.e. cholesterol) and non-sterol (i.e. isoprenoid) products of MVA metabolism exert coordinated feedback regulation on HMGCR through different mechanisms. The proper functioning of HMGCR as the proximal enzyme in the MVA pathway is essential under both normal physiologic conditions and in many diseases given its role in cell cycle pathways and cell proliferation, cholesterol biosynthesis and metabolism, cell cytoskeletal dynamics and stability, cell membrance structure and fluidity, mitochondrial function, proliferation, and cell fate. The blockbuster statin drugs ('statins') directly bind to and inhibit HMGCR, and their use for the past thirty years has revolutionized the treatment of hypercholesterolemia and cardiovascular diseases, in particular coronary heart disease. Initially thought to exert their effects through cholesterol reduction, recent evidence indicates that statins also have pleiotropic immunomodulatory properties independent of cholesterol lowering. In this review we will focus on the therapeutic applications and mechanisms involved in the MVA cascade including Rho GTPase and Rho kinase (ROCK) signaling, statin inhibition of HMGCR, geranylgeranyltransferase (GGTase) inhibition, and farnesyltransferase (FTase) inhibition in cardiovascular disease, pulmonary diseases (e.g. asthma and chronic obstructive pulmonary disease (COPD), and cancer).en_US
dc.description.sponsorshipA career-developing award provided by the Parker B Francis Foundation supported Saeid Ghavami. Pawan Sharma was supported by a CIHR postdoctoral fellowship award. Amir A.Zeki was supported by the National Center for Advancing Translational Sciences, National Institutes of Health (NIH), through grant #UL1 TR000002; and CTSC NIH KL2 (K12) Award TR000134.en_US
dc.identifier.citationPharmacology and Therapeutics, 2014en_US
dc.identifier.doihttp://dx.doi.org/10.1016/j.pharmthera.2014.02.007
dc.identifier.issn0163-7258
dc.identifier.urihttp://hdl.handle.net/1993/23336
dc.language.isoengen_US
dc.publisherElsevieren_US
dc.rightsopen accessen_US
dc.subjectstatinsen_US
dc.subjectasthmaen_US
dc.subjectcanceren_US
dc.subjectchronic obstructive pulmonary diseaseen_US
dc.subjectfibrosisen_US
dc.titleTargeting the Mevalonate Cascade as a New Therapeutic Approach in Heart Disease, Cancer and Pulmonary Diseaseen_US
dc.typeArticleen_US
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