Peroxisome proliferator-activated receptors for hypertension

Abstract

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear receptor superfamily, which is composed of four members encoded by distinct genes (α, β, γ, and δ). The genes undergo transactivation or transrepression under specific mechanisms that lead to the induction or repression of target gene expression. As is the case with other nuclear receptors, all four PPAR isoforms contain five or six structural regions in four functional domains; namely, A/B, C, D, and E/F. PPARs have many functions, particularly functions involving control of vascular tone, inflammation, and energy homeostasis, and are, therefore, important targets for hypertension, obesity, obesity-induced inflammation, and metabolic syndrome in general. Hence, PPARs also represent drug targets, and PPARα and PPARγ agonists are used clinically in the treatment of dyslipidemia and type 2 diabetes mellitus, respectively. Because of their pleiotropic effects, they have been identified as active in a number of diseases and are targets for the development of a broad range of therapies for a variety of diseases. It is likely that the range of PPARγ agonist therapeutic actions will result in novel approaches to lifestyle and other diseases. The combination of PPARs with reagents or with other cardiovascular drugs, such as diuretics and angiotensin II receptor blockers, should be studied. This article provides a review of PPAR isoform characteristics, a discussion of progress in our understanding of the biological actions of PPARs, and a summary of PPAR agonist development for patient management. We also include a summary of the experimental and clinical evidence obtained from animal studies and clinical trials conducted to evaluate the usefulness and effectiveness of PPAR agonists in the treatment of lifestyle-related diseases.

Keywords: Peroxisome proliferator-activated receptors, Nuclear receptor, Isoform, mRNA, Blood pressure, Hypertension, Obesity, Angiotensin II receptor blocker, Diabetes mellitus

Core tip: Lifestyle-related diseases are major public health problem worldwide, and the prevalence of these diseases and subsequent complications has increased rapidly over the past 20 years. It has been a decade or more since the first report of the pleiotropic effects of peroxisome proliferator-activated receptors (PPARs), and numerous studies on their novel effects continue to appear every month. In addition to their effects on blood pressure, atherosclerosis, and kidney dysfunction, anti-cancer effects of PPARγ ligands have been reported recently. The effectiveness of PPAR agonists in the treatment of lifestyle-related diseases will be increasingly appreciated. This review summarizes the current literature on PPARs.