High molecular weight Advanced Glycated End Products cause reduced and slower cell shortening by decreasing I_CaL

Abstract

Advanced glycated end-products (AGEs) are proteins and lipids that become glycated and oxidized after persistent contact with reducing sugars or short-chain aldehydes. There is growing evidence reporting that AGEs with a high molecular weight (HMW-AGEs) contribute to the development and progression of cardiovascular dysfunction in vivo. Therefore, rats were daily injected intraperitoneally for 6 weeks with either HMW-AGEs (20 mg/kg/day, n=25) or a control solution (n=19). Echocardiographic and hemodynamic measurements were performed at sacrifice to assess global cardiac function. Single cardiomyocytes from the left ventricle were obtained by enzymatic dissociation through retrograde perfusion of the aorta. Unloaded cell shortening was measured during field stimulation at 1, 2 and 4 Hz. Finally, Ca2+ influx, as assessed by L-type Ca2+ current (ICaL), was measured during whole-cell ruptured patch. After 6 weeks of HMW-AGEs injection, rats displayed in vivo cardiac dysfunction as characterized by a significant increased wall thickness and changes in peak rate pressure rise and decline. In addition, single cardiomyocytes were significantly wider. Unloaded cell shortening was significantly reduced in HMW-AGEs and was associated with slower kinetics. Finally, peak ICaL density was significantly decreased in HMW-AGEs injected animals. Altogether, our data indicate that HMW-AGEs induce cardiac dysfunction related to altered excitation-contraction coupling at the cellular level.