Oleuropein Ameliorates Isoproterenol‐Induced Cardiac Hypertrophy Through Sirtuin‐1 Activation via Endoplasmic Reticulum Stress Inhibition

ABSTRACT Cardiac hypertrophy is a major risk factor for cardiovascular disease worldwide, and Mediterranean diet has shown great benefits in reducing cardiovascular disease‐related mortality and morbidity. Numerous studies have ascertained that the protective effect of olive oil on the heart is mainly attributed to its active component, oleuropein (OLE); however, the mechanism remains unknown. We hypothesised that OLE provides cardioprotective effects against cardiac hypertrophy through the alleviation of endoplasmic reticulum stress. In the present study, different dosage regimens (10, 30 and 60 mg/kg) of OLE were intragastrically administered to an isoproterenol (ISO) (7.5 mg/kg)‐induced cardiac hypertrophy mouse model. OLE alleviates ISO‐induced cardiac hypertrophy and apoptosis. In addition, the increased expression of endoplasmic reticulum (ER) stress‐related genes, such as Glucose‐Regulated Protein 78 (GRP78), activating transcription factor 4 (ATF4), CCAAT/enhancer‐binding protein homologous protein (CHOP), and protein kinase RNA‐like ER kinase (PERK), was blunted by OLE, with reduced Sirtuin‐1 (SIRT1) levels. Furthermore, after pretreatment with EX527 (a SIRT1 inhibitor), the anti‐hypertrophic, anti‐apoptosis and ER stress effects of OLE were diminished, implying a key role of SIRT1 in ER stress inhibition. Our study indicates that OLE ameliorates ISO‐induced cardiac hypertrophy through SIRT1 activation via ER stress inhibition.