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

Abstract

Macro-and microvascular disease states currently represent the principal causes of morbidity and mortality in patients with type I or type II diabetes mellitus. Abnormal vasomotor responses and impaired endothelium-dependent vasodilation have been demonstrated in various beds in different animal models of diabetes and in humans with type I or type II diabetes. Several mechanisms leading to endothelial dysfunction have been reported, including changes in substrate avail ability, impaired release of NO, and increased destruction of NO. The principal mediators of diabetes-associated endothelial dysfunction are (a) increases in oxidized low density lipoprotein, endothelin-1, angiotensin II, oxidative stress, and (b) decreases in the actions of insulin or growth factors in endothelial cells. An accumulating body of evidence indicates that abnormal regulation of the phosphatidylinositol 3-kinase (PI3-K)/Akt pathway may be one of several factors contributing to vascular dysfunction in diabetes. The PI3-K pathway, which activates serine/threonine protein kinase Akt, enhances NO synthase phosphorylation and NO production. Several studies suggest that in diabetes the relative ineffectiveness of insulin and the hyperglycemia act together to reduce activity in the insulin-receptor substrates (IRS)/PI3-K/Akt pathway, resulting in impairments of both IRS/PI3-K/Akt-mediated endothelial function and NO production. This article summarizes the PI3-K/Akt pathway-mediated contraction and relaxation responses induced by various agents in the blood vessels of diabetic animals.

Acetylcholine-induced vasodilation in the perfused kidney of the streptozotocin-induced diabetic rat: role of prostacyclin

“…decreased production of one of the EDRFs, enhanced inactivation of EDRF, impaired diffusion of EDRF to the underlying smooth muscle cells, decreased responsiveness of the smooth muscle to EDRF, and/or enhanced generation of EDCFs (Poston and Taylor, 1995;De Vriese et al, 2000b;Fitzgerald et al, 2005;Kobayashi et al, 2004Kobayashi et al, , 2005Matsumoto et al, 2004b). In vascular tissues in diabetes, ACh-induced relaxation appears to be blunted by the synthesis of an endothelium-derived constrictor prostanoid(s) (Tesfamariam et al, 1989).…”

“…In fact, renal hemodynamic changes may make an important contribution to diabetic nephropathy, and it is well known that vascular disease is one of the complicating features of diabetes mellitus in humans (Anderson and Vora, 1995;Sowers and Epstein, 1995). The reactivity of vascular smooth muscle and the endothelium to vasoactive agents has been extensively studied in diabetes in both experimental animals and humans (Poston and Taylor, 1995;De Vriese et al, 2000b;Fitzgerald et al, 2005;Kobayashi et al, 2004Kobayashi et al, , 2005Matsumoto et al, 2004b). Concerning the macrovasculature, an accumulating body of evidence suggests that the relaxation responses induced in the aorta by endothelium-dependent agents are weaker in streptozotocin (STZ)-induced diabetic animals than in non-diabetic control animals (Kamata et al, 1989De Vriese et al, 2000b;Kobayashi et al, 2000).…”

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

“…They do this by responding to mechanical forces and neurohumoral mediators with the release of a variety of contracting [endothelium-derived contracting factors (EDCFs)] and relaxing factors [endothelium-derived relaxing factors (EDRFs)] (Cohen, 2005;Kamata et al, 1989;Kobayashi et al, 2005;Matsumoto et al, 2004aMatsumoto et al, , 2006aPieper, 1998;Triggle et al, 2003;Vanhoutte et al, 2005). A balanced release of these bioactive factors facilitates vascular homeostasis.…”

“…There is an accumulating body of evidence to show that in several vessels, the endotheliumdependent relaxation responses are weaker in experimental models of cardiovascular diseases and in patients with such diseases (De Vriese et al, 2000;Kamata et al, 1989;Kobayashi et al, 2000Kobayashi et al, , 2005Poston and Taylor, 1995;Sekiguchi et al, 2004;Triggle et al, 2003). Further, improvements in such impaired relaxation responses have been reported following treatment with a PPARγ agonist.…”

“…Indeed, impaired endothelial NO production participates in the pathogenesis of a number of cardiovascular diseases Landmesser et al, 2004;Pieper, 1998). In ECs, endothelial NO synthase (eNOS) produces NO from the amino acid L-arginine, and eNOS itself is regulated not only at the level of expression (Drummond et al, 2000), but also post-translationally [by mechanisms including interactions of eNOS with other proteins (Garcia-Cardena et al, 1998;Murata et al, 2002;Sessa, 2005) and eNOS phosphorylation (Du et al, 2001;Kobayashi et al, 2005)]. For example, specific stimuli including histamine, vascular endothelial growth factor (VEGF), and shear stress have been shown to activate eNOS by promoting its interaction with heat shock protein 90 (hsp90), a molecular chaperone protein (Garcia-Cardena et al, 1998).…”