Low-dose EUK-8 ameliorated survival, improved left ventricular function, and attenuated cardiac hypertrophy and fibrosis in both Hq mutant and wild-type mice subjected to pressure overload.
Does EUK-8 improve survival and reduce cardiac remodeling in Hq mutant and WT mice subjected to pressure overload?
EUK-8 protects against pressure overload-induced heart failure in both oxidative stress-prone Hq mice and WT mice, suggesting a potential therapeutic role for mitochondrial antioxidants in heart failure.
The purpose of this study was to identify apoptosis-inducing factor (AIF) as a cardiac mitochondrial antioxidant and assess the efficacy of EUK-8, a salen-manganese catalytic free radical scavenger, to protect the AIF-deficient myocardium against pressure overload.Oxidative stress has been postulated to provoke cell death and pathologic remodeling in heart failure. We recently characterized the apoptosis-inducing factor-deficient harlequin (Hq) mouse mutant to display excessive pressure overload-induced oxidative stress, cell death, accelerated progression to heart failure, and a reduced capacity of subsarcolemmal mitochondria to scavenge free radicals, suggesting a role for AIF as a novel mitochondrial antioxidant.Oxidative stress-sensitized Hq mutant mice and their wild-type (WT) counterparts were given low-dose EUK-8 (25 mg/kg/day), an antioxidant with superoxide dismutase, catalase, and oxyradical scavenging properties, or vehicle for 4 weeks, and subjected to pressure overload (transverse aortic constriction) for 4 weeks. Myocardial geometry and function was serially assessed by echocardiography.EUK-8 ameliorated survival in Hq and WT mice subjected to pressure overload. EUK-8 also improved left ventricular end-systolic dimensions and fractional shortening, prevented myocardial oxidant stress, attenuated necrotic and apoptotic cell death, and attenuated cardiac hypertrophy and fibrosis in both mutant and WT mice.The protection against pressure overload-induced heart failure in Hq mice by EUK-8 substantiates the notion that AIF functions as an important mitochondrial antioxidant in the heart. Furthermore, because antioxidant treatment protected both the oxidative stress-prone Hq mouse model and WT mice against pressure overload-induced maladaptive left ventricular remodeling and cardiac decompensation, it may be useful as a novel therapeutic tool in the treatment of human heart failure. Original language English Pages (from-to) 824-832 Journal Journal of the American College of Cardiology Volume 48 Issue number 4 DOIs https://doi.org/10.1016/j.jacc.2006.02.075 Publication status Published - 1 Jan 2006
Empel et al. (Wed,) conducted a other in Pressure overload-induced heart failure. EUK-8 vs. Vehicle was evaluated on Survival, left ventricular end-systolic dimensions, fractional shortening, myocardial oxidant stress, cell death, cardiac hypertrophy and fibrosis. Low-dose EUK-8 ameliorated survival, improved left ventricular function, and attenuated cardiac hypertrophy and fibrosis in both Hq mutant and wild-type mice subjected to pressure overload.