Peroxisome proliferators activated receptors (PPARs) are
ligand-activated nuclear
transcription factors that play important roles in
lipid and
glucose homeostasis. To the extent that
PPAR agonists improve diabetic dyslipidaemia and
insulin resistance, these agents have been considered to reduce cardiovascular risk. However, data from murine models suggests that
PPAR agonists also have independent anti-atherosclerotic actions, including the suppression of vascular
inflammation, oxidative stress, and activation of the renin angiotensin system. Many of these potentially anti-atherosclerotic effects are thought to be mediated by transrepression of nuclear factor-kB, STAT, and
activator protein-1 dependent pathways. In recent clinical trials,
PPARalpha agonists have been shown to be effective in the primary prevention of cardiovascular events, while their cardiovascular benefit in patients with established
cardiovascular disease remains equivocal. However, the use of
PPARgamma agonists, and more recently dual
PPARalpha/gamma coagonists, has been associated with an excess in cardiovascular events, possibly reflecting unrecognised fluid retention with potent agonists of the
PPARgamma receptor. Newer pan agonists, which retain their anti-atherosclerotic activity without
weight gain, may provide one
solution to this problem. However, the complex biologic effects of the PPARs may mean that only vascular targeted agents or pure transrepressors will realise the goal of preventing atherosclerotic
vascular disease.