Copyright © 2008 Brian N. Finck et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
The PPAR family of nuclear
receptor transcription factors are important regulators of cardiovascular
function and metabolism. Because of this, PPARs are potentially interesting
pharmacologic targets for treating cardiometabolic disease. The reviews in this
series discuss the regulatory functions of PPARs in maintaining metabolic and
physiologic homeostasis in a variety of cells and tissues. Additionally, the
therapeutic potential and mechanisms of action of ligands of the different PPAR
isotypes are discussed.
The review
series is started by an examination of the effects of PPARs on lipoprotein
metabolism. This is one of the first identified functions of PPARs. Indeed,
ligands for PPARα were in
clinical use as lipid-lowering agents even before their pharmacological target,
PPARα, were known.
The second review evaluates the important anti-inflammatory effects of PPARs in
platelets, which is emerging as an important mechanism of their beneficial
effects. Next, the critical role that PPARα and its transcriptional
coactivator protein PGC-1α play in regulating energy
metabolism and function of the myocardium is discussed. Then, a series of
reviews focuses on the potentially beneficial effects of PPARγ agonists
on the cardiovascular system. Several aspects are presented. The effects of
PPAR activation on the cardiovascular system as a whole, on the vascular smooth
muscle cell, and in the context of diabetic cardiovascular disease are each
discussed at length. A review by Demers et al. also discusses the potential input of the
hexarelin signaling pathway in regulating PPARγ activity and its potential impact
on cardiometabolic disease. The genes encoding the PPARs are rich with genetic
variation and the impact of these polymorphisms and haplotypes on the response
to PPAR activators is only beginning to be understood. Thus, the “pharmacogenomics”
of PPARs are discussed in a review by Dr. Sharon Cresci. Finally, the potential toxicity and
adverse outcomes of PPAR agonism are summarized in detail by Jennifer Robinson.
The timeliness of this discussion is outstanding given the recent reports of
increased cardiovascular morbidity associated with use of rosiglitazone and the
failure of PPAR dual agonists at different stages of development. Several of
the other reviews in this series also touch this controversial issue at
least briefly.
We are also
pleased to present two original research reports. The first report found
associations between PPARγ gene polymorphisms and several
cardiometabolic indices, but found no link with cardiovascular morbidity and
mortality. Second, Buroker
et al. report an important role for PGC-1α in postnatal metabolic maturation.
This preprogrammed burst in cardiac oxidative metabolism is an important
developmental response that also has implications for other physiologic states
wherein the demand for ATP production is rapidly induced.
We hope
that you will find this issue enjoyable and informative.
Brian N. Finck
Giulia Chinetti
Bart Staels