Protective effect of low dose gadolinium chloride against isoproterenol-induced myocardial injury in rat

Acute myocardial injury remains a leading cause of morbidity and mortality worldwide, and large amount of released arachidonic acid (AA) is found to be related to cardiomyocyte apoptosis and necrosis. Previous study suggested that GdCl3 completely abolished AA-induced Ca2+ response. Thus, this study aims to investigate possible cardioprotection effect of GdCl3 on isoproterenol (ISO)-induced myocardial injury and its underlying mechanism(s). Rats that were randomly allocated to five groups: control, GdCl3, ISO, ISO + GdCl3, and ISO + verapamil. Serum levels of AA and cardiac markers, infarct area, and cell apoptosis in heart were measured by ELISA assay, TTC and TUNEL staining, respectively. Chemical interaction between AA and GdCl3 was evaluated by mass and UV spectrometry. The expressions and translocations of death receptor related molecules into lipid rafts were detected in neonatal rat ventricular myocytes by Western blots. Compared with ISO-administered rats, GdCl3 significantly ameliorated the myocardium injury, demonstrated by restoring serum cardiac troponin I, lactate dehydrogenase, creatine kinase MB and AA to near normal levels, and decreasing infarct area and cell apoptosis. In addition, an activation of AA-Fas pathway was found in ISO-induced myocardial injury, which was abrogated by GdCl3. Furthermore, AA induced cell apoptosis through clustering and activating death receptor related molecules TNFR1, Fas and FADD in lipid rafts, a process significantly prevented by the pretreatment with GdCl3. Finally, GdCl3 at the molar ratio of 1/3 (GdCl3/AA) was mostly effective in abolishing AA-induced Ca2+ response and cell apoptosis, because an obvious change in the chemical identity of AA was obtained by GdCl3 according to this molar ratio. In conclusion, this study demonstrates for the first time that GdCl3 protects myocardium against ISO-induced cell apoptosis through, at least partly, serving as a scavenger of AA, therefore abolishing its downstream activation of the death receptor regulated apoptosis pathway.