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: Behzad Yeganeh, Emilia Wiechec, Sudharsana R Ande, Pawan Sharma, Adel Rezaei Moghadam, Martin Post, Darren H Freed, Mohammad Hashemi, Shahla Shojaei, Amir A Zeki, Saeid Ghavami
• Journal: Pharmacology & therapeutics (Pharmacol Ther) Vol. 143 Issue 1 Pg. 87-110 (Jul 2014) ISSN: 1879-016X [Electronic] England
• PMID: 24582968 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Review)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Hydroxymethylglutaryl CoA Reductases
• Alkyl and Aryl Transferases
• geranylgeranyltransferase type-I
• Farnesyltranstransferase
• rho-Associated Kinases
• rho GTP-Binding Proteins
• Mevalonic Acid

Topics

• Alkyl and Aryl Transferases (antagonists & inhibitors)
• Animals
• Cardiovascular Diseases (drug therapy)
• Farnesyltranstransferase (antagonists & inhibitors)
• Humans
• Hydroxymethylglutaryl CoA Reductases (physiology)
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (pharmacology, therapeutic use)
• Lung Diseases (drug therapy)
• Mevalonic Acid (metabolism)
• Neoplasms (drug therapy)
• Pulmonary Disease, Chronic Obstructive (drug therapy)
• rho GTP-Binding Proteins (antagonists & inhibitors, physiology)
• rho-Associated Kinases (antagonists & inhibitors, physiology)