Will the potential of peroxisome proliferator-activated receptor agonists be realized in the clinical setting?

Abstract

Drugs targeting both peroxisome proliferator‐activated receptor‐gamma (PPAR‐γ) agonists (the thiazolidinediones) and PPAR‐α (the fibrates) have already been developed for clinical use. However, the thiazolidinediones, currently prescribed to treat hyperglycemia and improve peripheral insulin resistance, may also have cardiovascular benefits that have yet to be fully realized. Animal models of atherosclerosis have shown that the thiazolidinediones reduce the extent of atherosclerotic lesions and inhibit macrophage accumulation. Clinical studies have also shown that these drugs improve the lipid profile of patients at risk of developing atherosclerosis and reduce circulating levels of inflammatory markers. This combination of lower lipid concentrations and reduced inflammation may explain the cardiovascular benefits of this class of drugs. Early trials in patients with coronary stents have reported promising findings, with restenosis rates being greatly reduced with thiazolidinedione therapy. It is hoped that the results of future clinical trials will continue to be encouraging, so that the thiazolidinediones' cardiovascular benefits can be fully realized in the clinic.

Endotoxin, TLR4 Signaling and Vascular Inflammation: Potential Therapeutic Targets in Cardiovascular Disease

“…The most direct evidence for this anti-inflammatory role comes from studies with PPARα -/-mice. These mice exhibit a prolonged inflammatory response to the PPARα agonist leukotriene B4 (LTB4), and aortic tissue from these mice exhibits a relatively greater inflammatory response to endotoxin relative to wild-type controls [239,241,249]. Because PPARγ deficiency is embryonic lethal, studies similar to those with PPARα -/-mice are not possible; however, heterozygous (PPARγ +/-) mice are more susceptible to experimentallyinduced inflammatory bowel disease and arthritis than are their wild-type littermates [240].…”

“…All three isoforms of PPAR (PPARα, PPARβ/δ, PPARγ ) appear to play an anti-inflammatory role in many tissues [239][240][241][242], including endothelial cells, smooth muscle cells, and leukocytes (monocytes/macrophages, T cells, neutrophils) [242][243][244].…”

Peroxisome Proliferator‐Activated Receptors: Potential Therapeutic Targets in Lung Disease?

“…Relative to wild-type controls, these mice exhibit a prolonged inflammatory response to the PPARa agonist leukotriene B 4 (LTB 4 ), and aortic tissue from these mice exhibits a relatively greater inflammatory response to LPS. 7,21,78 PPARaÀ/À mice also show defects in wound-healing. Since PPARg deficiency is embryoniclethal, studies similar to those with PPARaÀ/À mice are not possible.…”

“…7,[19][20][21] These publications are recommended to readers who want additional information on these topics. The present review focuses on the body of knowledge related to the expression, function, and regulation of PPARs, with specific emphasis on their potential roles in lung homeostasis and disease.…”

“…2,7,15,24 In addition to their other functions, all PPAR isoforms appear to play important roles in inflammation and immunity. 7,[19][20][21]25,26 In lung tissue, both PPARa and PPARg are expressed in alveolar macrophages and airway epithelial cells. 6,13 PPARb/d is also expressed in primary airway epithelial cells, and to a lesser extent in epithelial cell lines.…”