What is the clinical evidence from this study?

Study design: Other. Population: Diabetic cardiomyopathy. Intervention: Streptozotocin (STZ) and High Glucose vs. Vehicle / Normal glucose. Primary outcome: Cardiac function and hypertrophic marker expression.

October 18, 2023Open Access

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

UFUrszula FlorczykJagiellonian University KPKatarzyna PolakJagiellonian University RSReece SaboJagiellonian University

Key Result

Streptozotocin-induced hyperglycemia promoted cardiac hypertrophy and dysfunction independently of miR-378a, despite miR-378a upregulation in the diabetic milieu.

Structured PICO

Does miR-378a upregulation mediate hyperglycemia-driven cardiac hypertrophy and dysfunction in diabetic cardiomyopathy models?

Population

Preclinical study using male wild-type and miR-378a knockout mice, along with human induced pluripotent stem cell-derived cardiomyocytes, to evaluate the role of miR-378a in diabetic cardiomyopathy.

Intervention

Streptozotocin (STZ) 55 mg/kg i.p. for 5 days (in vivo model); high glucose (55 mM) treatment for 48 hours (in vitro model).

Comparator

Citrate buffer vehicle (in vivo model); basal glucose (11 mM) or mannitol (55 mM) osmotic control (in vitro model).

Outcome

Cardiac function assessed by high-resolution ultrasound imaging in vivo, and IGF-1R pathway activation/hypertrophic marker expression.surrogate

Although miR-378a is upregulated in hyperglycemic conditions, its presence or absence does not affect the overall decline in cardiac function in diabetic cardiomyopathy, pointing to miR-378a-independent mechanisms of hyperglycemia-driven cardiac dysfunction.

Limitations

The 8-week study period upon STZ treatment may not be sufficient to observe severe effects of miR-378a deficiency on overall cardiac function.
STZ-driven hyperglycemia did not affect the extent of fibrotic lesions and collagen expression in this experimental setting.

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.

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