title: Targeting the mevalonate cascade as a new therapeutic approach in heart disease, cancer and pulmonary disease.
abstract: The 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 membrane 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.
authors.affiliation: Hospital for Sick Children Research Institute, Department of Physiology & Experimental Medicine, University of Toronto, Toronto, Canada.
authors.forename: Behzad
authors.initials: B
authors.lastname: Yeganeh
authors.affiliation: Dept. Clinical & Experimental Medicine, Division of Cell Biology & Integrative Regenerative Med. Center (IGEN), Linköping University, Sweden.
authors.forename: Emilia
authors.initials: E
authors.lastname: Wiechec
authors.affiliation: Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Sudharsana R
authors.initials: SR
authors.lastname: Ande
authors.affiliation: Department of Physiology & Pharmacology, Snyder Institute for Chronic Diseases, Faculty of Medicine, University of Calgary, 4C46 HRIC, 3280 Hospital Drive NW, Calgary, Alberta, Canada.
authors.forename: Pawan
authors.initials: P
authors.lastname: Sharma
authors.affiliation: Scientific Association of Veterinary Medicine, Faculty of Veterinary Medicine, Tabriz Branch, Islamic Azad University, Tabriz, Iran; Young Researchers and Elite Club, Ardabil Branch, Islamic Azad University, Ardabil, Iran.
authors.forename: Adel Rezaei
authors.initials: AR
authors.lastname: Moghadam
authors.affiliation: Hospital for Sick Children Research Institute, Department of Physiology & Experimental Medicine, University of Toronto, Toronto, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Post
authors.affiliation: Department of Physiology, St. Boniface Research Centre, University of Manitoba, Winnipeg, Canada.
authors.forename: Darren H
authors.initials: DH
authors.lastname: Freed
authors.affiliation: Cellular and Molecular Research Center, Zahedan University of Medical Sciences, Zahedan, Iran.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Hashemi
authors.affiliation: Department of Biochemistry, Recombinant Protein Laboratory, Medical School, Shiraz University of Medical Sciences, Shiraz, Iran.
authors.forename: Shahla
authors.initials: S
authors.lastname: Shojaei
authors.affiliation: U.C. Davis, School of Medicine, U.C. Davis Medical Center, Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, Center for Comparative Respiratory Biology & Medicine, Davis, CA, USA. Electronic address: amir.zeki@ucdmc.ucdavis.edu.
authors.forename: Amir A
authors.initials: AA
authors.lastname: Zeki
authors.affiliation: Department of Human Anatomy and Cell Science, St. Boniface Research Centre, Manitoba Institute of Child Health, Biology of Breathing Theme, University of Manitoba, Winnipeg, Canada. Electronic address: ghavami@cc.umanitoba.ca.
authors.forename: Saeid
authors.initials: S
authors.lastname: Ghavami
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors; D000818:Animals; D002318:Cardiovascular Diseases / Q000188:drug therapy*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000502:physiology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D008171:Lung Diseases / Q000188:drug therapy*; D008798:Mevalonic Acid / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy*; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000502:physiology
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D006903:Hydroxymethylglutaryl CoA Reductases; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D051231:Farnesyltranstransferase; D054460:rho-Associated Kinases; D020741:rho GTP-Binding Proteins; D008798:Mevalonic Acid
keywords: Asthma; Farnesyl transferase inhibitors; Fibrosis; Geranylgeranyl transferase inhibitors; Rho GTPase; Statins