GDF11 Mitigates Diabetic Cardiomyopathy Injury Via Regulation of the ALKBH5-FOXO3-CDR1as/Hippo Pathway

Background: Diabetic cardiomyopathy has threatened the lives and health of more and more people. Growth differentiation factor 11 (GDF11) plays a crucial role within the cardiovascular system. Still, GDF11 was not clearly described in diabetic cardiomyopathy. Methods: Firstly, we used echocardiography to detect the heart function of mice. Secondly, we used qRT-PCR, western blot, CCK8 analysis, LIVE /DEAD and TUNEL analysis to evaluate cell viability and apoptosis, and then used dual-luciferase reporter assay, quantitation of m6A RNA methylation assay, RIP experiment and constructed cardiac-specific GDF11 knock-in mice to explore molecular mechanisms. Findings: Our preliminary results showed that GDF11 expression decreased in DCM mice. Exogenous GDF11 could mitigate cardiomyocyte apoptosis caused by high glucose. Mechanistically, GDF11 restrained CDR1as/Hippo signaling pathway, which was activated by high glucose. As a transcriptional factor of CDR1as, FOXO3 was identified to activate the Hippo signaling pathway. Notably, the total m6A level was downregulated in the cardiac tissue of DCM. ALKBH5 was upregulated in the cardiomyocytes of DCM mice and posttranscriptionally activated FOXO3 by m6A demethylation in an m6A-YTHDF2-dependent manner. Furthermore, we verified that GDF11 could inhibit ALKBH5-FOXO3-CDR1as/Hippo signaling by using the GDF11 cardiac-specific knock-in mice. Interpretation: In general, our results demonstrated that application of GDF11 or inhibition of ALKBH5-FOXO3-CDR1as/Hippo signaling pathway may be new strategies for use to treat DCM. Funding: This work was supported in part by the National Natural Science Foundation of China (Grants Nos.81670238 and 81970320). Declaration of Interest: The authors declare no competing interests. Ethical Approval: The Ethics Committee of Harbin Medical University approved this research.