OBJECTIVE: To explore whether Rhein can inhibit acute myocardial infarction–induced endoplasmic reticulum and mitochondrial stress through activating the phosphatidylinositol 3-kinase/serine/threonine kinase/ extracellular signal regulated kinase (PI3K/Akt/ERK) pathway. METHODS: A rat model of myocardial infarction was established. The cardiac function injury was detected by echocardiography. The apoptosis of cardiomyocytes was detected by transferase-mediated dUTP-biotin nick end labeling (TUNEL) fluorescence staining. The endoplasmic reticulum–related proteins C/EBP homology protein (CHOP), glucose-regulated protein 78 (GRP78), and cysteine-containing aspartate-specific proteases 12 (caspase-12), as well as mitochondrial cytochrome c, Bcl-2 associated X protein (Bax), and B-cell lymphoma 2 (Bcl-2) were detected by immunofluorescence staining. Western blot assay was employed to detect the expression of CHOP, GRP-78, activating transcription factor 6 (ATF-6), Bcl-2, Bax, AKT, and ERK proteins. RESULTS: Rhein could effectively improve cardiac dysfunction caused by acute myocardial infarction. Rhein can effectively protect cardiomyocytes and reduce apoptosis. Rhein significantly inhibited the expressions of endoplasmic reticulum CHOP, GRP-78, and other proteins; reduced the expressions of mitochondria-associated proteins such as cytochromec, Bax, and Bcl-2; elevated the expressions of p-AKT and p-ERK proteins; and inhibited PARP expression in the myocardial infarct area. CONCLUSION: Rhein can significantly reduce apoptosis induced by acute myocardial infarction injury in rats, which requires the activation of Akt and ERK signaling pathways and the inhibition of endoplasmic reticulum stress and mitochondrial dysfunction-associated proteins. © Science Printers and Publishers Inc.