Relationship between peroxisome proliferator‐activated receptors (PPARα and PPARγ) and endothelium‐dependent relaxation in streptozotocin‐induced diabetic rats

Abstract

1 The aim of the present study was to investigate the causal relationship between peroxisome proliferator-activated receptor (PPAR) and endothelium-dependent relaxation in streptozotocin (STZ)-induced diabetic rats. 2 Acetylcholine (ACh)-induced endothelium-dependent relaxation was significantly weaker in diabetic rats than in age-matched controls. The decreased relaxation in diabetes was improved by the chronic administration of bezafibrate (30 mg kg À1 , p.o., 4 weeks). 3 The expressions of the mRNAs for PPARa and PPARg were significantly decreased in STZinduced diabetic rats (compared with the controls) and this decrease was restored partially, but not completely, by the chronic administration of bezafibrate. 4 Superoxide dismutase activity in the aorta was not significantly different between diabetic rats and bezafibrate-treated diabetic rats. 5 The expression of the mRNA for the p22phox subunit of NAD(P)H oxidase was significantly higher in diabetics than in controls, but it was lower in bezafibrate-treated diabetic rats than in nontreated diabetic rats. Although the expression of the mRNA for prepro ET-1 (ppET-1) was markedly increased in diabetic rats (compared with controls), this increase was prevented to a significant extent by the chronic administration of bezafibrate. 6 These results suggest that downregulations of PPARa and PPARg may lead to an increased expression of ppET-1 mRNA in diabetic states and this increment may trigger endothelial dysfunction.

The PI3-K/Akt pathway: roles related to alterations in vasomotor responses in diabetic models

“…Furthermore, we found that chronic administration of a relatively low dose of bezafibrate, which was insufficient to alter the levels of plasma lipids (including total cholesterol, LDL cholesterol, high density lipoprotein (HDL) cholesterol, and triglyceride), exerted an improvement effect on the endothelial dysfunction seen in the aorta in rats with established STZ-induced diabetes. This effect of bezafibrate may result from a reduction in the NAD(P)H oxidase p22phox subunit through an inhibitory effect on ET-1 synthesis (Kanie et al, 2003).…”

Relationships among ET-1, PPAR.GAMMA., oxidative stress and endothelial dysfunction in diabetic animals

“…In such animals, we previously reported that: (1) the plasma ET-1 level is increased and that this increase may be due to an overexpression of the mRNA for prepro-ET-1 (Makino and Kamata, 1998;Makino et al, 2001), (2) the overproduction of ET-1 seen in STZ-induced diabetes results from the hyperglycemia, not from any increase in either LDL cholesterol or triglyceride (Makino and Kamata, 2000), (3) the expression of the mRNA for p22phox is increased in STZinduced diabetes, an increase that is completely preventable by the chronic administration of J-104132 (a potent, orally active, mixed antagonist of ETA and ETB receptors) (Kanie and Kamata, 2002), and (4) short-term or prolonged treatment with ET-1 impairs endothelial function in the aorta both in nondiabetic rats Matsumoto et al, 2007d) and in rats with established STZ-induced diabetes . Moreover, we have demonstrated that chronic administration of the PPARα agonist bezafibrate to established STZ-induced diabetic rats normalizes both the mRNA for prepro-ET-1 and the plasma concentration of ET-1, while improving endothelium-dependent relaxation (Kanie et al, 2003). In that paper, we also demonstrated that the expressions of the mRNAs for PPARα and PPARγ were downregulated in aortic segments from STZ-induced diabetic rats (Kanie et al, 2003).…”

“…Moreover, we have demonstrated that chronic administration of the PPARα agonist bezafibrate to established STZ-induced diabetic rats normalizes both the mRNA for prepro-ET-1 and the plasma concentration of ET-1, while improving endothelium-dependent relaxation (Kanie et al, 2003). In that paper, we also demonstrated that the expressions of the mRNAs for PPARα and PPARγ were downregulated in aortic segments from STZ-induced diabetic rats (Kanie et al, 2003). In the recent paper referred to above, we found that the elevated plasma ET-1 level seen in such established STZinduced diabetic rats can be largely suppressed by chronic treatment with pioglitazone, and that the increased expression of aortic c-Jun (an AP-1 component) seen in such rats is greatly reduced by the pioglitazone treatment (Matsumoto et al, 2007d).…”

“…A perturbation of the balance between ETA-and ETBreceptor activities may contribute to the pathogenesis of vascular disease (Brunner et al, 2006;Goto et al, 1996;Kanie and Kamata, 2002;Matsumoto et al, 2004c;Miyauchi and Masaki, 1999). Some, but not all, experimental models of hypertension, atherosclerosis, and diabetes display high levels of circulating ET-1, and exhibit endothelial dysfunction (Barton et al, 1998;Brunner et al, 2006;Kanie et al, 2003;Makino and Kamata, 1998). ET-1 has been linked to the production of superoxide within the vasculature in association with endothelial dysfunction (Elmarakby et al, 2005;Kamata et al, 2004;Lamplante et al, 2005;Li et al, 2003) (Fig.…”

Novel Anti-Diabetic Formula: Recover Islet ?-Cell dysfunction with the implementation of molecular approach

“…The hyperglycemia in both type 1 and type 2 diabetes mostly results from the loss of β-cell mass that would lead to considerable morbidity in the globe population. Lately, an option and promising approach in expansion is to stimulate the regeneration of endogenous β-cells to replace the deficit in β-cell mass in diabetic patients [45][46][47][48]. Peroxisome proliferator-activated receptor a (PPARα and PPARγ), which is activated by specific agonists as fatty acid and fibrates forms heterodimers associated with PPAR response elements in the promoter region of target genes and retinoid X receptor [49].…”