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Astragaloside IV (AS-IV), the major active constituent purified from Astragalus membranaceus , was previously reported to have protective effects against cardiac dysfunction. However, the underlying mechanism remains unknown. In the present study, we investigated the protective effect of AS-IV on lipopolysaccharide (LPS)-induced cardiac dysfunction and explored the potential mechanism by focusing on miRNA-1 (miR-1) at the animal and cellular levels. A series of methods were used, including echocardiography, flow cytometry, ELISA, immunofluorescence, transmission electron microscopy, RT-PCR, and western blotting. The results showed that both AS-IV and the miR-1 inhibitor improved cardiac dysfunction, reduced heart injury, inhibited apoptosis and autophagy, and regulated the expression of calcium- and mitochondrial energy metabolism-related proteins in the heart tissue of rats treated with LPS. Importantly, AS-IV downregulated the expression of miR-1 mRNA in heart tissue. All effects of AS-IV were at least partly abolished by miR-1 mimics. In the in vitro study, both AS-IV and the miR-1 inhibitor inhibited apoptosis and autophagy and regulated the expression of calcium- and mitochondrial energy metabolism-related proteins in heart cells treated with LPS. Similarly, AS-IV downregulated the expression of miR-1 mRNA in heart cells. All effects of AS-IV on cells were at least partly abolished by miR-1 mimics. Furthermore, miR-1 mimics exhibited effects similar to LPS both in animal and cellular studies. Taken together, these results suggest that AS-IV protects against LPS-induced cardiac dysfunction by inhibiting calcium-mediated apoptosis and autophagy by targeting miR-1, highlighting a new mechanism for the therapeutic effect of AS-IV on cardiac dysfunction. [ABSTRACT FROM AUTHOR]