STRA13 exacerbates T2DM-induced diabetic cardiomyopathy by regulating the RXRα/UCP-1 signaling pathway.

STRA13, a basic helix-loop-helix protein superfamily member, is a CLOCK gene. Previous studies have reported the role of STRA13 in regulating blood pressure. However, the role of STRA13 in diabetic cardiomyopathy (DCM) has not been fully elucidated. In this study, STRA13 full knockout mice were subjected to a high-fat diet (HFD) to induce DCM. We found that STRA13 was upregulated in both heart tissue and cardiomyocytes undergoing metabolic disorders. STRA13 knockout ameliorated HFD-induced cardiac dysfunction, fibrosis, mitochondrial dysfunction and cell apoptosis. STRA13 deficiency also protected against HFD-induced glucose and lipid metabolism disorders. STRA13 overexpression in mice worsened HFD-induced cardiac dysfunction, fibrosis, and injury. STRA13 overexpression in cardiomyocytes worsened high glucose-induced cell injury, mitochondrial dysfunction and oxidative stress. STRA13 silencing in cardiomyocytes protected against the high glucose (HG)-induced alterations described above. Moreover, STRA13 was found to downregulate retinoid X receptor alpha (RXRα), resulting in reduced expression of uncoupling protein 1 (UCP-1). Co-IP confirmed that STRA13 interacted with RXRα. A luciferase assay confirmed that RXRα regulated the transcription of UCP-1. Silencing of STRA13 did not protect cardiomyocytes from HG-induced injury caused by RXRα or UCP-1 knockdown. Cardiac overexpression of UCP-1 also blunted the deteriorating effects of STRA13. However, STRA13 inhibited RXRα nuclear expression, which hampered the protective effects of RXRα overexpression in vivo. Taken together, our findings demonstrate that STRA13 exacerbates diabetic cardiomyopathy by impairing mitochondrial function through the disruption of RXRα-UCP-1 signaling. Therefore, targeting the STRA13-RXRα-UCP-1 axis may represent a promising therapeutic strategy for mitigating mitochondrial dysfunction and cardiac injury in the context of DCM.