Diabetic cardiomyopathy (DCM) is a common complication in diabetic patients. The molecular mechanisms of DCM remain to be fully elucidated. The intronic
long noncoding RNA of DACH1 (lncDACH1) has been demonstrated to be closely associated with
heart failure and cardiac regeneration. In this study, we investigated the role of lncDACH1 in DCM and the underlying molecular mechanisms. The expression of lncDACH1 was increased in DCM hearts and in high
glucose-treated cardiomyocytes. Knockout of lncDACH1 reduced mitochondrial oxidative stress, cell apoptosis, cardiac
fibrosis and
hypertrophy, and improved cardiac function in DCM mice. Overexpression of lncDACH1 exacerbated mitochondria-derived
reactive oxygen species (ROS) level and apoptosis, decreased activity of
manganese superoxide dismutase (
Mn-SOD); while silencing of lncDACH1 attenuated ROS production,
mitochondrial dysfunction, cell apoptosis, and increased the activity of
Mn-SOD in cardiomyocytes treated with high
glucose. LncDACH1 directly bound to sirtuin3 (
SIRT3) and facilitated its degradation by ubiquitination, therefore promoting mitochondrial oxidative injury and cell apoptosis in mouse hearts. In addition,
SIRT3 silencing abrogated the protective effects of lncDACH1 deficiency in cardiomyocytes. In summary, lncDACH1 aggravates DCM by promoting mitochondrial oxidative stress and cell apoptosis via increasing ubiquitination-mediated
SIRT3 degradation in mouse hearts. Inhibition of lncDACH1 represents a novel therapeutic strategy for the intervention of
diabetic cardiomyopathy.