Abstract Body (Do not enter title and authors here): Background and Aims: Diabetes mellitus usually causes cardiac dysfunction and heart failure. However, little is known about the trigger at the early stage of diabetic cardiac dysfunction.
Methods: Recombinant adeno-associated virus serotype 9 carrying UBAP1 (ubiquitin associated protein 1) shRNA under cardiac troponin T promoter was injected into db/db mice in vivo. High glucose incubated neonatal rat ventricular myocytes and AC16 cell line were used to imitate diabetic cardiomyopathy in vitro. To explore the mechanism, flow cytometry, Western blotting, JC-1 measurement, ribosome profiling, mass spectrometry analysis, co-immunoprecipitation and dual-luciferase reporter assays were conducted.
Results: UBAP1 was identified as the stable increased protein in diabetic cardiomyopathy at early stage. The specific depression of UBAP1 in cardiomyocytes of db/db mice improved cardiac function and attenuated cardiomyocyte hypertrophy as well as apoptosis. Mechanistically, UBAP1 could stabilize SLC25A4, the key target responsible for mitochondrial permeability transition pore opening, thereby causing cardiomyocyte apoptosis in the heart. Ribosome profiling and matched mRNA sequencing of hearts of eight-week-old db/db and bks mice revealed that the translation efficiency of UBAP1 was elevated at early stage. Furthermore, high glucose inhibited Na⁺/K⁺-ATPase activity and decreased intracellular potassium level consequently. The intracellular potassium deficiency destabilized the RNA G-quadruplex (rG4) structure at UBAP1 mRNA 5’UTR and facilitated the translation of UBAP1.
Conclusions: Our findings provide a novel mechanism at the initiate stage of diabetic cardiac dysfunction that early inhibited Na⁺/K⁺-ATPase activity and intracellular potassium deficiency could trigger constant elevation of UBAP1, promoting mitochondrial dysfunction and cell apoptosis in the diabetic heart, suggesting a potential therapeutic target for diabetic cardiomyopathy.