Compromised diabetic heart function is not affected by miR-378a upregulation upon hyperglycemia

Abstract

Background Cardiac-abundant microRNA-378a (miR-378a) is associated with postnatal repression of insulin–like growth factor 1 receptor (IGF-1R) controlling physiological hypertrophy and survival pathways. IGF-1/IGF-1R axis has been proposed as a therapeutic candidate against the pathophysiological progress of diabetic cardiomyopathy (DCM). We ask whether hyperglycemia-driven changes in miR-378a expression could mediate DCM progression. Methods Diabetes mellitus was induced by streptozotocin (STZ) (55 mg/kg i.p. for 5 days) in male C57BL/6 wild type (miR-378a+/+) and miR-378a knockout (miR-378a−/−) mice. As a parallel human model, we harnessed human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM miR378a+/+ vs. hiPSC-CM miR378a−/−) subjected to high glucose (HG) treatment. Results We reported miR-378a upregulation in cardiac diabetic milieu arising upon STZ administration to wild-type mice and in HG-treated hiPSC-CMs. Pro-hypertrophic IGF-1R/ERK1/2 pathway and hypertrophic marker expression were activated in miR-378a deficiency and upon STZ/HG treatment of miR-378a+/+ specimens in vivo and in vitro suggesting miR-378a-independent hyperglycemia-promoted hypertrophy. A synergistic upregulation of IGF-1R signaling in diabetic conditions was detected in miR-378a−/− hiPSC-CMs, but not in miR-378a−/− hearts that showed attenuation of this pathway, pointing to the involvement of compensatory mechanisms in the absence of miR-378a. Although STZ administration did not cause pro-inflammatory or pro-fibrotic effects that were detected in miR-378a−/− mice, the compromised diabetic heart function observed in vivo by high-resolution ultrasound imaging upon STZ treatment was not affected by miR-378a presence. Conclusions Overall, data underline the role of miR-378a in maintaining basal cardiac structural integrity while pointing to miR-378a-independent hyperglycemia-driven cardiac hypertrophy and associated dysfunction.

Roles of non-coding RNA in diabetic cardiomyopathy

“…Multiple miRNAs have been identified to modulate cardiac hypertrophy and fibrosis in DCM. Anti-hypertrophic miRNAs, such as miR-1 [ 25 ], miR-133a [ 26 ], miR-373 [ 27 ], miR-181a [ 28 ], miR-150 [ 22 ], miR-30c [ 29 ], miR-378a [ 30 ], miR-29a [ 31 ] and miR-200c [ 32 ]. Pro-hypertrophic miRNAs include miR-208a [ 33 ], miR-451 [ 34 ], miR-214, miR-212 [ 35 ], miR-221 [ 36 ], miR-195, miR-125b [ 37 ] and miR-199a [ 38 ].…”