shikonin and Heart-Failure

Shikonin is a naphthoquinone compound extracted from the root of Lithospermum with various pharmacological activities. Sympathetic neural remodeling greatly contributes to chronic heart failure. Growing evidence has identified a critical role of microRNAs (miRNAs) in a variety of cardiac biological processes. This study aimed to verify whether shikonin could attenuate sympathetic neural remodeling and explore the possible regulatory role of miRNAs in this process.. Shikonin was administered to mice after transverse aortic constriction (TAC). Immunohistochemistry and western blotting were used to assess the expression of TAC-induced sympathetic remodeling-related proteins.. TAC-induced expression of the sympathetic remodeling-related proteins, tyrosine hydroxylase (TH), growth associated protein 43 (GAP43), choline acetyltransferase (ChAT), vesicular acetylcholine transporter (VAChT), and nerve growth factor (NGF), was significantly decreased in cardiac tissues. MiR-124 expression significantly increased after heart failure and decreased after shikonin treatment. An adeno-associated virus 9 (AAV9) vector was packaged and used to transfect myocardial tissues of aortic-constricted mice with miR-124, resulting in increased heart miR-124 levels and inhibition of the effects of shikonin on sympathetic neural remodeling. Immunohistochemical staining showed that the density of TH-, GAP43-, and ChAT-positive nerves was significantly increased in aortic-constricted mice after transfection with AAV9-miR-124.. Our data demonstrate that shikonin administration prevents sympathetic neural remodeling in mice with TAC-induced heart failure. The effects of shikonin on heart failure may be partly due to miR-124-mediated attenuation of sympathetic remodeling. Our results reveal a novel mechanism underlying the therapeutic effect of shikonin in heart failure.

Topics: Animals; Cardiotonic Agents; Chronic Disease; Constriction, Pathologic; GAP-43 Protein; Gene Expression Regulation; Heart Failure; Male; Mice, Inbred C57BL; MicroRNAs; Myocardium; Naphthoquinones; Sympathetic Nervous System; Vesicular Acetylcholine Transport Proteins

Shikonin, isolated from the roots of herbal plant Lithospermum erythrorhizon, is a naphthoquinone. It has been reported to exert beneficial anti-inflammatory effects and anti-oxidant properties in various diseases. Isoproterenol (ISO) has been widely used to establish cardiac injury in vivo and in vitro. However, shikonin function in ISO-induced cardiac injury remains uncertain. In our study, we attempted to investigate the efficiency and possible molecular mechanism of shikonin in cardiac injury treatment induced by ISO. In vivo, C57BL6 mice were subcutaneously injected with 5mg/kg ISO to induce heart failure. And mice were given a gavage of shikonin (2 or 4mg/kg/d, for four weeks). Cardiac function, fibrosis indices, inflammation response, apoptosis and endoplasmic reticulum (ER) stress were calculated. Pathological alterations, fibrosis-, inflammation-, apoptosis- and ER stress-related molecules were examined. In ISO-induced cardiac injury, shikonin significantly ameliorated heart function, decreased myocardial fibrosis, suppressed inflammation, attenuated apoptosis and ER stress through impeding collagen accumulation, Toll like receptor 4/nuclear transcription factor κB (TLR4/NF-κB), Caspase-3 and glucose-regulated protein 78 (GRP78) signaling pathways activity, relieving heart failure in vivo. Also, in vitro, shikonin attenuated ISO-induced cardiac muscle cells by reducing fibrosis, inflammation, apoptosis and ER stress. Our findings indicated that shikonin treatment attenuated ISO-induced heart injury, providing an effective therapeutic strategy for heart failure treatment for future.

Topics: Animals; Apoptosis; Cardiomyopathies; Caspase 3; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Fibrosis; Gene Expression Regulation; Heart; Heart Failure; HSP70 Heat-Shock Proteins; Inflammation; Isoproterenol; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Myocardium; Myocytes, Cardiac; Naphthoquinones; NF-kappa B