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

Abstract

Macro-and microvascular disorders currently represent the principal causes of morbidity and mortality in patients with diseases involving the cardiovascular system, such as atherosclerosis, hypertension, stroke, and diabetes. Abnormal vasomotor responses and impaired endothelium-dependent vasodilation have been demonstrated in a number of vessels in a variety of animal models and in humans with such diseases. Endothelial dysfunction plays a key role in the development of these diseases, yet the genesis of this endothelial dysfunction and its associated vasomotor abnormalities remain poorly understood. Peroxisome proliferator-activated receptor (PPAR)γ is a nuclear receptor and transcription factor in the steroid superfamily, and PPARγ agonists (the thiazolidinediones) are used clinically to treat type 2 diabetes. Recent studies have revealed that as well as being involved in adipogenesis and in increased sensitivity to insulin, PPARγ plays critical roles in the vasculature. In the present review, we discuss the beneficial effects of PPARγ agonists on vasomotor activities, focusing in particular on endothelium-dependent relaxation in vessels affected by cardiovascular diseases.

PPAR‐γ – a possible drug target for complicated pregnancies

“…In particular, ligand-induced activation of PPAR-g attenuated the microparticle-mediated up-regulation of NF-kB transcription, expression and activation, which ultimately prevented increases in both interleukin (IL)-6 and IL-8 (Tesse et al, 2008). In both monocytes and macrophages, PPAR-g activation has been shown to reduce the production of cytokines including TNF-a (Hofmann et al, 1994), IL-1b and IL-6 via the inhibition of pro-inflammatory transcription factors such as AP-1, STAT and NF-kB (see Figure 1; Jiang et al 1998;Ricote et al 1998;Barak et al 2002;Matsumoto et al 2008). Furthermore, PPAR-g activation suppresses the expression of pro-inflammatory adhesion molecules including intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1) and E-selectin (Wang et al, 2002), which would reduce the increase in adherence of monocytes to both endothelial and polymorphonuclear cells (Imamoto et al, 2004).…”

Inhibition of JAK/STAT signaling pathway prevents high-glucose-induced increase in endothelin-1 synthesis in human endothelial cells

“…The up-regulation of ET-1 is frequently associated with endothelial dysfunction that precedes cardiovascular diseases associated with diabetes mellitus (Matsumoto et al 2008). Our results support and extend the previous reports (Hargrove et al 2000;Marrero et al 2006) showing the stimulatory effect of high glucose on ET-1 mRNA expression and secretion.…”

“…Although the published reports show that nuclear factor kappa B (NF-kB) and activating protein-1 (AP-1) are crucial regulators of stimuli-induced ET-1 transcription (Matsumoto et al 2008;Quehenberger et al 2000), this information provides no further insight into the molecular mechanisms responsible for the increased expression of ET-1 in diabetes-associated vascular disorders. Nevertheless, data regarding the role of the JAK/ STAT cascade in the regulation of ET-1 synthesis are lacking.…”

“…In addition, peroxisome proliferator-activated receptor-γ (PPARγ) agonists have been demonstrated to be able to suppress ET-1 secretion (Matsumoto et al 2008). Data from murine models suggest that the anti-atherosclerotic effects of PPARγ agonists might be mediated by the trans-repression of NFkB-, STAT-, and AP-1-dependent pathways (Calkin and Thomas 2008).…”

“…In addition to its vasoactive function, it has been implicated in mitogenesis and has a pro-inflammatory and profibrotic effect. ET-1 up-regulation has been associated with endothelial dysfunction in atherosclerosis, hypertension, and diabetes (Matsumoto et al 2008;Schiffrin and Touyz 1998). Nevertheless, the underlying mechanisms accountable for the increased ET-1 level are not completely defined.…”