MiR-451 antagonist protects against cardiac fibrosis in streptozotocin-induced diabetic mouse heart.

AIMS: MicroRNAs (miRNAs or miRs) are a large class of small noncoding RNAs. The present study aims to evaluate the effect of miR-451 on cardiac remodeling in diabetic cardiomyopathy.

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METHODS

Mice were injected with streptozotocin (STZ) to induce diabetes. Twelve weeks after final STZ injection, mice were subjected to myocardial injection of adenovirus (Ad)-shmiR-451 to knock down miR-451. Mouse heart endothelial cells (MHECs) were treated with a miR-451 antagomir to inhibit miR451 and were exposed to high glucose.

KEY FINDINGS: Sixteen weeks after STZ injection, mice exhibited no significant cardiac hypertrophy but did exhibit serious cardiac fibrosis. MiR-451 knockdown attenuated cardiac fibrosis and improved cardiac function. Moreover, we found that miR-451 knockdown suppressed endothelial-to-mesenchymal transition (EndMT) in diabetic mouse hearts. Hyperglycemia-induced EndMT in MHECs was attenuated by the miR-451 antagomir. Activation of AMPKa1/mTOR was decreased in diabetic mouse heart tissue and hyperglycemia-stimulated MHECs, which was increased following miR-451 knockdown or inhibition. AMPKa1 siRNA abrogated the anti-EndMT effects of miR-451 knockdown in MHECs.

SIGNIFICANCE: miR-451 participates in the pathology of diabetic cardiomyopathy via AMPKa1-regulated EndMT in endothelial cells.