Atrial APD prolongation caused by the upregulation of RAGE and subsequent INaL increase in diabetic patients

Abstract

Diabetes mellitus (DM) is a risk factor for the development of atrial fibrillation (AF). The action potential duration (APD) has been demonstrated to be prolonged in the atrium of diabetic mice. In contrast, the APD is generally shortened in AF patients. It is unclear what change occurs in the atrial APD of diabetic patients. In this study, we explore the APD change of atrial myocytes from diabetic patients and the underlying molecular mechanisms. The whole-cell patch-clamp technique is used to detect single-cell electrical activity in diabetic and nondiabetic human samples. The results show that both APD50 and APD90, the APD at 50% and 90% repolarization, are increased in diabetic patients compared with those in nondiabetic controls. The density of late sodium current (INaL) in the atrial myocytes of diabetic patients is greater than that in the myocytes of nondiabetic patients. The expression of receptor for advanced glycation end products (RAGE) is increased in the atria of diabetic patients. In cultured HL-1 cells, high glucose (HG) treatment increases INaL, and the expression of RAGE prolongs APD. The siRNA-mediated knockdown of RAGE reduces the INaL and shortens the APD. The APD is prolonged in the atria of diabetic patients because of the upregulation of RAGE and the subsequent increase in INaL. Our findings provide novel insights into atrial electrical remodeling in diabetic patients.

1. Introduction

There is an increased risk of arrhythmias in diabetic patients due to structural and functional alterations in the heart [1]. Diabetic patients are approximately 1.4–2.1 times more prone to developing atrial fibrillation (AF) than nondiabetic patients are [2–4]. Alteration of action potential duration (APD) in atrial myocytes is a major determinant of atrial arrhythmia susceptibility. Although shortening of the APD is a well-established mechanism for the development of AF, the APD has been demonstrated to be prolonged in diabetic animal models [5]. Iuliia et al. [6] reported that the APD was prolonged in the right and left atria of type 1 diabetic Akita mice, which was accompanied by increased susceptibility to AF. Fu et al. [7] reported that the action potential duration was prolonged in atrial myocytes isolated from Zucker diabetic fatty (ZDF) rats compared with Zucker lean (ZL) rats. Liu et al. [8] reported that hyperglycemia contributes to prolonging APD90 and APD50 in diabetic rabbits, resulting in atrial electrical remodeling for the development and perpetuation of AF. To the best of our knowledge, there is a lack of direct evidence showing changes in atrial APD in diabetic patients.

Multiple ion channel currents have been demonstrated to be altered in the atrium of diabetic patients and are believed to contribute to the increased APD. Yi et al. [9] demonstrated that downregulation of the L-type calcium current (ICaL) is related to prolonged atrial APD in diabetic rabbits. We previously reported that the mRNA and protein levels of Cav1.2 were significantly reduced in atrial myocytes isolated from the atria of type 2 diabetic rats [10]. Fu et al. [11] reported that increased ICaL and decreased INa currents were reflected in prolonged APD90 and APD50 values in alloxan-induced diabetic rabbits. An increase in the late sodium current can significantly affect the duration of action potential in cardiomyocytes and plays a key role in arrhythmogenesis [12]. INaL was found to be increased in the atrial myocytes of atrial fibrillation patients, and blocking INaL has been shown to exert anti-AF effects [12,13]. Our previous research confirmed that an increased late sodium current contributes to the prolongation of APD, which is associated with increased susceptibility to atrial fibrillation in diabetic mice [14].

The receptor for advanced glycation end products (RAGE), a pattern-recognizing receptor for multiple ligands, has many functions, including cell migration, proliferation, and inflammatory responses [15]. Lv et al. [16] reported that RAGE mRNA and protein expression are upregulated in the hearts and kidneys of diabetic mice fed with a high-advanced glycation end products (AGEs) diet. Kato et al. [17] reported that RAGE was abundant in the atrium of diabetic rats. Advanced AGEs and RAGE are responsible for atrial ...