Heart failure after myocardial infarction (MI) is associated with the aggregation of collagen and some misfolded proteins.This study was aimed to assess the therapeutic efficacy of doxycycline (Dox) in MI-induced heart failure and elucidate the potential mechanisms involved.A heart failure model of animals was established by ligating the left anterior descending coronary artery of rats.The administration of Dox via drinking water (25 mg/kg/day) was initiated after surgery and lasted for two weeks.After cardiac function evaluation by echocardiography, all animals were killed to assess the aggregation of type Ⅰ collagen, atrial natriuretic peptide (ANP), and the activities of matrix metalloproteinases (MMPs), autophagosomes and microtubule-associated protein 1 light chain 3 (LC3).Dox treatment significantly improved cardiac function and attenuated cardiac hypertrophy.Histological observation revealed that Dox significantly reduced the expression of collagen and ANP in the heart, Further investigation showed that Dox significantly inhibited the activities of MMP-2 and MMP-9, increased autophagosomes and enhanced LC3-Ⅱ in post-infarction hearts.This study revealed that Dox treatment could promote autophagy, reduce ANP aggregation in post-infarction hearts, and inhibit MMP-2 and MMP-9 activities.Dox might act as a potential therapeutic drug for preventing proteotoxicity and cardiac dysfunction.