O-GlcNAcase inhibition by Thiamet G opposes acute cardiac decompensation in rats with chronic heart failure

Abstract

Exacerbation of heart failure (HF), better known as acute decompensated HF, is characterized by dyspnea, edema and fatigue, which is associated with a high morbi-mortality. O-linked β-N-acetylglucosamine (O-GlcNAc) is a key regulator of the cellular stress response and increased O-GlcNAc levels exerts protective effects in models of acute vascular injury and ischemia-reperfusion injury. However, whether increasing O-GlcNAc exerts similar protective effects in acute decompensation of HF is unknown. We evaluated the cardiac effects of increasing O-GlcNAc levels by inhibiting O-GlcNAcase with Thiamet G (TG) in a rat model of acute decompensated HF. Three months after coronary artery ligation resulting in established HF, rats received 2.5 ml water (control) or 1.8 g/kg NaCl (dissolved in 2.5 ml water) provoking acute decompensation. Left ventricular (LV) fractional shortening and cardiac output (echography) as well as LV tissue perfusion (MRI) were assessed 1 and 14 days after NaCl-loading, and TG was administered 12 hours after NaCl (25 mg/kg IP). NaCl provoked acute decompensation in rats with HF. Indeed, 1 day after NaCl, the HF-related impairments of LV fractional shortening, cardiac output and myocardial tissue perfusion were aggravated. Fourteen days after NaCl, cardiac output partially recovered, but fractional shortening and myocardial perfusion remained impaired. As soon as 12 hours after administration, TG improved fractional shortening, cardiac output and tended to increase myocardial perfusion. Moreover, 14 days after TG, cardiac output and myocardial perfusion were still improved. These data show that in an experimental model salt-induced acute decompensation of HF, a curative treatment with TG improves both cardiac output as well as myocardial perfusion. The cellular mechanisms, i.e. post-translational protein O-GlcNAcylation, implicated in the effects of TG, are currently under investigation.