A　prolonged　or　excessive　adrenergic　activation　leads　to　myocyte　loss　and　heart　dysfunction;　however,　how　it　contributes　to　heart　failure　remains　poorly　defined.　Here　we　show　that　isoproterenol　(ISO)　induced　aberrant　endoplasmic　reticulum　(ER)　stress　and　apoptotic　cell　death,　which　was　inhibited　by　activating　the　AMP-activated　protein　kinase　(AMPK)　in　vitro　and　in　vivo.　Persistent　ISO　stimulation　suppressed　the　AMPK　phosphorylation　and　function,　resulting　in　enhanced　ER　stress　and　the　subsequent　cell　apoptosis　in　cardiomyocytes　in　vitro　and　in　vivo.　AMPK　activation　decreased　the　aberrant　ER　stress,　apoptosis,　and　brain　natriuretic　peptide　(BNP)　release　in　ISO-treated　cardiomyocytes,　which　was　blocked　by　AMPK　inhibitor　Compound　C.　Importantly,　increased　ER　stress　and　apoptosis　were　observed　in　ISO-treated　cardiomyocytes　isolated　from　AMPK　alpha　2(-/-)　mice.　Inhibition　of　ER　stress　attenuated　the　apoptosis　but　failed　to　reverse　AMPK　inhibition　in　ISO-treated　cardiomyocytes.　Moreover,　metformin　administration　activated　AMPK　and　reduced　both　ER　stress　and　apoptosis　in　ISO-induced　rat　heart　failure　in　vivo.　We　conclude　that　ISO,　via　AMPK　inactivation,　causes　aberrant　ER　stress,　cardiomyocyte　injury,　BNP　release,　apoptosis,　and　hence　heart　failure　in　vivo,　all　of　which　are　inhibited　by　AMPK　activation.