The O-GlcNAcase inhibitor ASN90 opposes acute cardiac decompensation in rats with chronic heart failure
G Vincent, C Hennion, C Corruble, C Fauvel, M Valet, B Angehrn-Pavik, B Permanne, P MulderAbstract
Background
Acute decompensated heart failure (ADHF) is characterized by dyspnea, edema and fatigue, associated with a high morbi-mortality. O-linked β-N-acetylglucosamine (O-GlcNAc) is a key regulator of the cellular stress response and increasing O-GlcNAc levels by O-GlcNAcase inhibition exerts protective effects in models of acute vascular injury or ischemia-reperfusion injury. The O-GlcNAcase inhibitor Thiamet G administered during the early phase of ADHF exerts cardiac protective effects, but whether this is 1) a class effects of O-GlcNAcase inhibition and 2) whether O-GlcNAcase inhibition initiated during the late phase of ADHF affords cardiac protection as observed after immediate O-GlcNAcase inhibition is unknown.
Objective
We assessed whether the O-GlcNAcase inhibitor ASN90 initiated during either the immediate or the late phase of ADHF improves cardiac function.
Methods
Four 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. Cardiac output (echography) was assessed before, 1, 6, 7 and 14 days after NaCl-loading, and the OGA-inhibitor ASN90 (30 mg/kg, PO) was administered either 12 hours or 6 days after NaCl-loading. Exercise capacity was determined using a treadmill.
Results
NaCl provoked acute decompensation in rats with HF. Indeed, 1 day after NaCl, the HF-related impairment of cardiac output was aggravated and only partially recovered during the 14 days. OGA-inhibitor ASN90 improved cardiac output, as soon as 12 hours after OGA-inhibitor ASN90 administrated either 12 hours or 6 days after NaCl-loading, and this beneficial effect persisted throughout the observation period (figure 1.A). Moreover, this improvement of cardiac function was associated with an increased running distance (figure 1.B).
Conclusions
These data show that in an experimental model of salt-induced ADHF, curative treatments with the O-GlcNAcase inhibitor ASN90 initiated during the immediate or the late phase of ADHF improve cardiac output to the same extent, and the improved cardiac function is associated with an increased exercise capacity.Effect of O-GlcNAcase inhibitor ASN90For image description, please refer to the figure legend and surrounding text.