Targeting the mevalonate cascade as a new therapeutic approach in heart disease, cancer and pulmonary disease

Behzad Yeganeh, Emilia Wiechec, Sudharsana R. Ande, Pawan Sharma, Adel Rezaei Moghadam, Martin Post, Darren H. Freed, Mohammad Hashemi, Shahla Shojaei, Amir Zeki, Saeid Ghavami

Research output: Contribution to journalArticle

93 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)87-110
Number of pages24
JournalPharmacology and Therapeutics
Volume143
Issue number1
DOIs
StatePublished - 2014

Keywords

  • Asthma
  • Farnesyl transferase inhibitors
  • Fibrosis
  • Geranylgeranyl transferase inhibitors
  • Rho GTPase
  • Statins

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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  • Cite this

    Yeganeh, B., Wiechec, E., Ande, S. R., Sharma, P., Moghadam, A. R., Post, M., Freed, D. H., Hashemi, M., Shojaei, S., Zeki, A., & Ghavami, S. (2014). Targeting the mevalonate cascade as a new therapeutic approach in heart disease, cancer and pulmonary disease. Pharmacology and Therapeutics, 143(1), 87-110. https://doi.org/10.1016/j.pharmthera.2014.02.007