Adrenergic signaling and oxidative stress: a role for sirtuins?

Graziamaria Corbi,Giuseppe Furgi,Nicola Ferrara,Valeria Conti,Amelia Filippelli,Giancarlo Longobardi,Giusy Russomanno

doi:10.3389/fphys.2013.00324

Graziamaria Corbi, Giuseppe Furgi + Show 5 more

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https://doi.org/10.3389/fphys.2013.00324

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Abstract

The adrenergic system plays a central role in stress signaling and stress is often associated with increased production of ROS. However, ROS overproduction generates oxidative stress, that occurs in response to several stressors. β-adrenergic signaling is markedly attenuated in conditions such as heart failure, with downregulation and desensitization of the receptors and their uncoupling from adenylyl cyclase. Transgenic activation of β2-adrenoceptor leads to elevation of NADPH oxidase activity, with greater ROS production and p38MAPK phosphorylation. Inhibition of NADPH oxidase or ROS significantly reduced the p38MAPK signaling cascade. Chronic β2-adrenoceptor activation is associated with greater cardiac dilatation and dysfunction, augmented pro-inflammatory and profibrotic signaling, while antioxidant treatment protected hearts against these abnormalities, indicating ROS production to be central to the detrimental signaling of β2-adrenoceptors. It has been demonstrated that sirtuins are involved in modulating the cellular stress response directly by deacetylation of some factors. Sirt1 increases cellular stress resistance, by an increased insulin sensitivity, a decreased circulating free fatty acids and insulin-like growth factor (IGF-1), an increased activity of AMPK, increased activity of PGC-1a, and increased mitochondrial number. Sirt1 acts by involving signaling molecules such P-I-3-kinase-Akt, MAPK and p38-MAPK-β. βAR stimulation antagonizes the protective effect of the AKT pathway through inhibiting induction of Hif-1α and Sirt1 genes, key elements in cell survival. More studies are needed to better clarify the involvement of sirtuins in the β-adrenergic response and, overall, to better define the mechanisms by which tools such as exercise training are able to counteract the oxidative stress, by both activation of sirtuins and inhibition of GRK2 in many cardiovascular conditions and can be used to prevent or treat diseases such as heart failure.

Highlights

The sympathetic adrenergic system plays a central role in stress signaling and stress is often associated with increased production of reactive oxygen species (ROS).ROS production is the result of several mechanisms, including generation during oxidative phosphorylation in the mitochondria as a product of normal cellular aerobic metabolism (Davies, 1995; Ide et al, 1999)
While tissue GRK2 levels have been correlated with plasma norepinephrine/epinephrine levels (Cho et al, 1999), GRK2 can be upregulated in cultured cells by chronic insulin (Garcia-Guerra et al, 2010), potentially as a result of PI3Kdependent stabilization of GRK2 (Salcedo et al, 2006). Both local/circulating G Protein-Coupled Receptors (GPCR) ligands associated with insulin resistance/hyperinsulinaemia, and insulin itself, contribute to the high GRK2 levels observed in insulin-resistant rodent/human tissues (Garcia-Guerra et al, 2010; Copps and White, 2012). These findings demonstrate that lowering GRK2 in myocytes after ischemic injury will contribute to restore cardiac metabolism and prevent the development of subsequent heart failure (Evron et al, 2012)
In the last decades several studies have demonstrated as the β-adrenergic system represents the target of the oxidative damage and, in turn, the responsible of oxidants production

Summary

INTRODUCTION

The sympathetic adrenergic system plays a central role in stress signaling and stress is often associated with increased production of reactive oxygen species (ROS). OXIDATIVE STRESS IN THE CARDIOVASCULAR SYSTEM Several in vitro and in vivo studies have demonstrated ROS activation in the cardiovascular system in response to various stressors and in the failing heart (Ide et al, 1999; Cesselli et al, 2001; Wallace, 2001; Sawyer et al, 2002; Sabri et al, 2003; Scortegagna et al, 2003; Suematsu et al, 2003), and animal studies have suggested that antioxidants and ROS defense pathways can ameliorate ROS-mediated cardiac abnormalities (Chen et al, 1996; Yen et al, 1996; Ho et al, 1998; Conrad et al, 2004; Giordano, 2005). It is widely known that oxidative stress and reduced antioxidant defense have negative effects on cardiac structure and function (Singal et al, 1988) and they are involved in lipid membrane oxidation and other heart age-related conditions (Corbi et al, 2012b). Ca2+ overload can be induced by direct effect of ROS on Ca2+ handling proteins or indirectly, by inducing membrane lipid peroxidation (Valko et al, 2007)

SIRTUINS AND OXIDATIVE STRESS IN THE CARDIOVASCULAR SYSTEM

Findings

CONCLUSIONS