EDEM2 is new therapeutic target for improving diabetes-induced cardiomyopathy by regulating DSG2

Abstract Introduction Diabetic cardiomyopathy (DCM) generally refers to myocardial dysfunction sorely caused by diabetes without any potential pathogeny. The mechanisms behind DCM have been explored for decades, but still not been well-established. Junctional complexes are a class of cellular structures providing contact or adhesion between neighbouring cells. Four types of junctional complexes are found in the intercalated disc (ID) of heart: adherens junction, desmosome and gap junction. Changes or mutations of junction proteins can result in a serious of cardiac disorder including heart failure (HF) and arrhythmia. EDEM2 (ER degradation enhancing alpha-mannosidase like protein 2) is responsible for degradation of misfolded N-glycosylated proteins, but its function in the heart is unknown. Purpose This study aims to examine the role of EDEM2 on DCM by regulating junction proteins. Methods C57BL/6J mice was used to induce type 1 diabetes by streptozotocin (STZ) injection. Cardiac function was assessed by echocardiography and morphological changes were determined by H&E staining, Masson’s staining and TUNEL staining. Immunochemistry (IHC) or immunofluorescence (IF) was performed to detect the location and expression of junction proteins. Membrane proteins were extracted, and western blot was applied to check DSG2 expression level. Results Junction proteins including N-cadherin (N-cad), connexin 43 (Cx43) and desmoglein 2 (DSG2) are decreased in the heart of patients diagnosed with DCM. EDEM2 is found lost in the hearts of diabetic mice models. Adeno-associated virus 9 (AAV9)-mediated deficiency of EDEM2 in mice leads to cardiac dysfunction and morphological changes upon STZ induction. The membrane level of DSG2, a transmembrane N-glycosylated protein belonging to desmosomes, is downregulated by EDEM2 global knockdown. On the contrary, AAV9-induced cardiac specific EDEM2 overexpression significantly improves cardiac performance, and inhibiting pathological progression, thus protecting the heart from failure. What’s more, DSG2 membrane level is restored by EDEM2 overexpression. Conclusions Our findings uncovered EDEM2 as a novel therapeutic target for improving DCM via regulating junction proteins. This novel therapeutic gene may present as a promising option for cardiac disease.