Abstract| Volume 23, ISSUE 10, SUPPLEMENT , S40, October 2017

Upregulation of AMP Deaminase in the Vicinity of the SR via Translational Regulation by miR-301b Contributes to Diabetic Cardiomyopathy

      Background: We recently reported that ATP loss by upregulated activity of AMP deaminase (AMPD) contributes to afterload-induced diastolic dysfunction in OLETF, type 2 diabetic rats. Here we examined the mechanism underlying the upregulation of AMPD. Methods and Results: Western blot analysis revealed that protein level of 90-kDa full-length AMPD3 was significantly increased in the sarcoplasmic reticulum (SR) fraction (117%) as well as in whole cell lysates (171%) in OLETF compared to its level in LETO, non-diabetic control rats. Levels of AMPD3 mRNA determined by RT-PCR was comparable in OLETF and LETO. Inhibitory effect of MG-132, a proteasome inhibitor, on degradation of the 90-kDa AMPD3 ex vivo was larger in OLETF than in LETO, arguing against suppressed degradation of AMPD3 in OLETF. MicroRNA array analysis revealed downregulation (>50%) of 57 microRNAs in OLETF compared to those in LETO. Transfection of H9c2 cells with an inhibitor of miR-301b, one of the 57 microRNAs, significantly increased level of the 90-kDa AMPD3. Binding of miR-301b to the 3'UTR of AMPD3 mRNA was confirmed by a luciferase reporter assay. Conclusion: Up-regulated AMPD3 translation by reduced miR-301b mediates increased AMPD3 in the diabetic heart. Since ATP generated by SR-associated glycolytic enzymes contributes to Ca2+ uptake by SERCA2a and promote diastolic relaxation, AMPD3 in the vicinity of the SR is a therapeutic target for diabetic cardiomyopathy.
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