Expression of Heme Oxygenase-1 in Human Vascular Cells Is Regulated by Peroxisome Proliferator-Activated Receptors

Abstract

Objective-Activation of peroxisome proliferator-activated receptors (PPARs) by lipid-lowering fibrates and insulinsensitizing thiazolidinediones inhibits vascular inflammation, atherosclerosis, and restenosis.

Peroxisome Proliferator-Activated Receptor-γ as a Potential Therapeutic Target in the Treatment of Preeclampsia

“…34 However, although PPAR-␥ agonists have been shown previously to restore proangiogenic factors, upregulate HO-1, 10 and increase the production of VEGF in vitro [35][36][37] and in vivo, 18 rosiglitazone failed to alter angiogenic factors in the RUPP rat in the present study. A recent study, involving the induction of HO-1 in RUPP rats via the administration of cobalt (III) protoporphyrin IX chloride, demonstrated that, as a result of cobalt (III) protoporphyrin IX chloride treatment, placental expression of HO-1 was increased, and there was a significant shift in the angiostatic balance ratio (sFlt-1:VEGF).…”

“…Thus, to see a beneficial effect of rosiglitazone on the sFlt-1/VEGF balance (as a consequence of alterations in placental HO-1 expression) it may be necessary to implement treatment at the point of surgical intervention (ie, RUPP surgery on GD14) as per cobalt (III) protoporphyrin IX chloride treatment. However, although rosiglitazone has been shown to upregulate HO-1 expression in both vascular smooth muscle and endothelial cells 10 it failed to do so in lung fibroblasts, 38 which may suggest a cell-specific effect that does not extend to the most abundant placental cell type, the trophoblast. Thus, in the present study, the beneficial effects of rosiglitazone, in terms of both vascular function and blood pressure, may simply be mediated by direct modulation of endothelial HO-1 activity, because these effects were abrogated by the HO-1 activity inhibitor SnPP.…”

“…The present study is one of the first to demonstrate a vasculoprotective role for PPAR-␥ in an animal model of preeclampsia and, in addition, proposes a role for HO-1 (antioxidant enzyme) in mediating this protective effect. Previous studies have shown that HO-1 is upregulated by PPAR-␥ agonists 10,24 and that HO-1 induction can prevent tumor necrosis factor-␣-induced endothelial dysfunction in vitro 25 ; thus, it may be possible that rosiglitazone protects the vasculature via an HO-1-dependent anti-inflammatory mechanism. The coadministration of SnPP with rosiglitazone ameliorated several of the effects observed after administration of rosiglitazone alone to the RUPP rat by inhibiting HO-1 expression under these experimental conditions.…”

“…9 To investigate the role of PPAR-␥ as a potential therapeutic target for preeclampsia, we administered the PPAR-␥ agonist, rosiglitazone, to rats that had undergone reduced uterine perfusion pressure (RUPP) surgery. As PPAR-␥ agonists have been shown to mediate some of their beneficial effects via upregulation of heme oxygenase 1 (HO-1), an antioxidant enzyme that negatively regulates soluble fms-like tyrosine kinase-1 (sFlt-1) expression, 10 we examined whether this enzyme played a role in any observed beneficial effects of rosiglitazone in the RUPP rat.…”

Treatment of Obese Diabetic Mice With a Heme Oxygenase Inducer Reduces Visceral and Subcutaneous Adiposity, Increases Adiponectin Levels, and Improves Insulin Sensitivity and Glucose Tolerance

“…Increase in adiponectin has been shown to improve the beneficial effects of antihypertensive agents in hypertensive patients (19). The peroxisome proliferator-activated receptor (PPAR)␥ response was found to increase expression of adiponectin (20) and also to regulate the expression of heme oxygenase (HO)-1 in human vascular cells (21).…”