Peroxisome Proliferator-Activated Receptor-α: Friend or Foe? Academic Article uri icon


  • he quest for better understanding for the pathophysiolog- ical basis of hypertension and atherosclerosis is ongoing. The complexity of hypertension and atherosclerosis and of the underlying mechanisms is becoming increasingly appar- ent. The number of candidate genes and molecular pathways that are involved is increasing in parallel. In the present issue of Hypertension, Tordjman et al1 explore the role of the candidate gene, peroxisome proliferator-activated receptor (PPAR)- (reviewed extensively and comprehensively in the Web site dedicated to PPAR:, in the regulation of blood pressure and atherogenesis. The investi- gators follow up their previous observation that PPAR- deficient mice were protected from hypertension and athero- sclerosis.2 They currently report that, in a mouse experimental model of high renin and elevated angiotensin II levels in which the PPAR gene has been knocked out, hypertension and diet-induced atherosclerosis are averted. PPAR is widely distributed in the vasculature, as well as in other tissues and organs. PPAR is a nuclear receptor, one in a family of at least 3 transcription factors that have been connected to cell metabolism and differentiation. The perox- isome, an intracellular organelle that is capable of self- replicating, is present in all eukaryotic cells that contain enzymes, some of which are oxidative enzymes. The effects of PPAR that we are currently dealing with, affecting blood pressure and atherogenesis, however, are thought not to be related to peroxisome proliferation or activation but rather to other intracellular pathways, some of which have been elucidated, whereas others remain to be clarified.3 PPAR has pleiotropic effects and controls multiple gene targets that involve, among others, fatty acid oxidation, lipid metabolism, and inflammatory/vascular pathways.3 As such, PPAR ac- tivity has been considered until now of benefit to the human organism. In the current study, Tordjman et al1 provide data that suggest that the absence of PPAR, not its presence or activation, is paradoxically associated with beneficial effects, such as prevention of the development of hypertension and attenuation of diet-induced atherosclerosis. Tordjman et al1 used in their study a transgenic mouse strain in which the human renin had been introduced along with the angioten- sinogen gene, resulting in high renin-high angiotensin-high aldosterone hypertension. The investigators knocked out in this particular model of hypertension the gene encoding PPAR, resulting in genomic disruption, which led to a significant reduction in active renin and aldosterone and a parallel reduction in the level of blood pressure and cardiac hypertrophy. Additional findings in that study were dimin- ished atherosclerosis at the aortic sinus and a reduction of foam cells in peritoneal macrophages. Fenofibrate, a PPAR activator, effectively increased blood pressure in the parental transgenic strain but did not affect blood pressure in the transgenic knockout strain. The investigators correctly con- cluded that, based on their findings in their specific mouse model, PPAR appears to fulfill a role in regulating blood pressure and atherogenesis. They further speculated that the mechanism whereby PPAR affects blood pressure involves the renin-angiotensin-aldosterone system. The simplicity and straightforward nature of the study

publication date

  • January 1, 2007