Proapoptotic and antiapoptotic effects of hyperglycemia: role of insulin signaling (1).

Abstract: Glucose toxicity is an important initiator of cardiovascular disease, contributing to the development of insulin resistance, impaired contractile function, abnormal energy metabolism, cardiomyocyte and endothelial cell death, coronary heart disease, and heart failure. High blood glucose can, however, paradoxically protect the heart against a variety of insults, including ischemia, hypoxia, and calcium overload. To provide information on the underlying basis of these divergent actions of high glucose, the present study examined the hypothesis that the adverse effects of high glucose are linked to impaired insulin signaling, leading to a reduction in the levels of cytoprotective factors, and that the beneficial effects of high glucose occur in the absence of insulin and result in an improvement in Akt signaling. This hypothesis was evaluated by using an in vitro cardiomyocyte model that is amenable to manipulations in glucose and insulin. Prolonged exposure of the isolated neonatal cardiomyocyte to medium containing insulin and high glucose led to increased susceptibility to angiotensin II-mediated apoptosis, an effect associated with reduced levels of phospho-Akt and an increased Bax/Bcl-2 ratio. By contrast, exposure to high glucose levels in the absence of insulin rendered the cardiomyocyte resistant to angiotensin II-mediated apoptosis. Because the beneficial effects of high glucose were associated with elevations in phospho-Akt and Bcl-2 content, the cardioprotective activity of high glucose resembles the actions of insulin. Hence, the activation state of Akt is largely determined by the activity of insulin and other growth factors. Because high glucose diminishes insulin signaling, it reduces phospho-Akt levels and renders the cell susceptible to damaging insults. In the absence of insulin, however, the natural activity of high glucose is unmasked. As a result, Akt signaling is increased and the cell is rendered resistant to cell death.

Key words: hyperglycemia, hyperglycemic preconditioning, insulin, apoptosis, Akt, angiotensin II.

Resume : La toxicite du glucose est un important facteur de declenchement de maladie cardiovasculaire, contribuant au developpement de l'insulinoresistance, a l'alteration de la fonction contractile, au dereglement du metabolisme energetique, a la mort des cardiomyocytes et des cellules endotheliales, a la coronaropathie et a l'insuffisance cardiaque. Paradoxalement, elle peut proteger le coeur contre une variete d'agressions, telles l'ischemie, l'hypoxie et la surcharge calcique. Pour mieux comprendre le fondement de ces diverses actions du glucose a fortes concentrations, la presente etude a examine l'hypothese que les effets indesirables d'une concentration elevee de glucose sont lies a une alteration de la signalisation de l'insuline, menant a une diminution des taux des facteurs cytoprotecteurs. En revanche, une concentration elevee de glucose a des effets benefiques en l'absence d'insuline et ameliore la signalisation Akt. Cette hypothese a ete examinee en utilisant un modele de cardiomyocyte in vitro conciliable avec des manipulations de glucose et d'insuline. Une exposition prolongee du cardiomyocyte neonatal isole a l'insuline et a une forte concentration de glucose a provoque une augmentation de la susceptibilite a l'apoptose vehiculee par l'angiotensine II, un effet associe a une reduction de la teneur en phospho-Akt et a une augmentation du rapport Bax/Bcl. A l'oppose, une exposition a une forte concentration de glucose en l'absence d'insuline a rendu le cadiomyocyte resistant a l'apoptose induite par l'angiotensine II. Comme les effets benefiques d'une forte concentration de glucose ont ete associes a des elevations de la teneur en phospho-Akt et en Bcl-2, l'activite cardioprotectrice du glucose a fortes concentrations ressemble aux actions de l'insuline. Ainsi, l'etat d'activation d'Akt est grandement determine par l'activite de l'insuline et d'autres facteurs de croissance. Comme le glucose a fortes concentrations diminue la signalisation de l'insuline, il reduit aussi la teneur en phospho-Akt et rend la cellule sensible aux agressions destructrices. Toutefois, en l'absence d'insuline, l'activite naturelle du glucose a fortes concentrations est devoilee, ce qui a pour resultat d'augmenter la signalisation Akt et de rendre la cellule resistante a l'apoptose cellulaire.

Mots-cles : hyperglycemie, preconditionnement hyperglycemique, insuline, apoptose, Akt, angiotensine II.

[Traduit par la Redaction]

Introduction

Cardiovascular disease is the major cause of mortality among diabetic patients. Not only are these patients at increased risk of coronary heart disease, but the outcome of an ischemic event is worse, raising the risk of developing heart failure. Another factor elevating the risk of developing heart failure is the increased rate of myocyte death (Aronson et al. 1997). Several studies have reported a direct effect of diabetes on cell death (Cai and Kang 2003; Frustaci et al. 2000). Moreover, chronic exposure of isolated cardiomyocytes to medium containing high glucose increases the rate of cell death (Fiordaliso et al. 2001; Shizukuda et al. 2002; Cai et al. 2002). Hyperglycemia has also been implicated in alterations in calcium transport, reactive species generation, and protein modification, events that can increase the severity of heart failure by causing …