Abstract

Ischemia heart disease , one of the lethal cardiovascular diseases, irreversibly impairs cardiac function and is recognized as the primary risk factor for mortality in industrialized countries. The myocardial ischemia treatment still faces a considerable degree of increasing unmet needs. Isosteviol sodium (STVNa) and its derivatives have been proven to effectively alleviate metabolic diseases , hypertension, and heart hypertrophy . Little is known about how STVNa confers the cardioprotective effect during acute myocardial ischemia (AMI). In the present study, a rat model of acute ST-segment–elevation myocardial ischemia by left anterior descending (LAD) ligation was established. Compared to the AMI model group, STVNa administration (4 mg/kg, twice a day) well preserved left ventricle function by ejection fraction (45.10 ± 10.39 vs. 73.64 ± 13.15, p  = 0.0013) and fractional shortening (22.94 ± 6.28 vs. 44.00 ± 11.05, p  = 0.0017). Further analysis shows that high-dose STVNa (4 mg/kg) significantly improved the hemodynamics in AMI rats, with LVSP (88.25 ± 12.78 vs 99.75 ± 5.10, p  = 0.018), max dP/dt (2978.45 ± 832.46 vs 4048.56 ± 827.23, p  = 0.096), LVEDP (19.88 ± 2.00 vs 22.26 ± 3.21, p  = 0.04) and left ventricular relaxation time constant (Tau) (0.030 ± 0.006 vs 0.021 ± 0.004, p  = 0.021). Mechanically, STVNa administration retained the myocardial levels of phosphorylated AMPK, and CPT1b. Moreover, STVNa significantly increased the total energy expenditure, and reduced fatty acid accumulation through mitochondrial oxidative phosphorylation , which was supported by the indirect calorimetry and cellular energy analysis. Taken together, these findings suggest that STVNa is a potential cardioprotection agent for ischemic cardiomyopathy , likely through improving energy homeostasis, left ventricular hemodynamics, and heart function.