ESC Heart Failure (Apr 2023)

MicroRNA‐155‐5p in serum derived‐exosomes promotes ischaemia–reperfusion injury by reducing CypD ubiquitination by NEDD4

  • Chenkai Hu,
  • Junyu Liao,
  • Ruiyan Huang,
  • Qiang Su,
  • Lei He

DOI
https://doi.org/10.1002/ehf2.14279
Journal volume & issue
Vol. 10, no. 2
pp. 1144 – 1157

Abstract

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Abstract Aims Recovery of blood flow is a therapeutic approach for myocardial infarction but paradoxically induces injury to the myocardium. Exosomes (exos) are pivotal mediators for intercellular communication that can be released by different cells and are involved in cardiovascular diseases. This study aimed to explore the possible effects and mechanisms of miR‐155‐5p loaded by serum‐derived exos in myocardial infarction reperfusion injury (MIRI). Methods and results Exos were isolated from mouse serum after induction of ischaemia reperfusion (I/R) and injected into I/R‐treated mice to assess cardiac function, infarction size, and cardiomyocyte apoptosis. Primary cardiomyocytes were transfected with miR‐155‐5p inhibitor before treatment with oxygen–glucose deprivation and re‐oxygenation (OGD/R) and exos derived from the serum of I/R‐treated mice (I/R‐Exos), in which Bcl‐2, Bax, and cleaved‐caspase‐3 levels were detected. The interactions among miR‐155‐5p, NEDD4, and CypD were evaluated. miR‐155‐5p level was evidently increased in I/R‐Exos than in exos from the serum of sham‐operated mice (P < 0.05). In comparison with the I/R group, the I/R‐Exos + I/R group had increased infarct size, elevated miR‐155‐5p expression, and boosted apoptotic rate in mouse myocardium (P < 0.05). In mice treated with I/R‐Exos and I/R, miR‐155‐5p inhibition reduced cardiac infarct size and apoptosis (P < 0.05). NEDD4 was a target gene of miR‐155‐5p and promoted CypD ubiquitination. Cardiomyocyte apoptosis was markedly increased in the miR‐155‐5p inhibitor + shNEDD4 + OGD/R group versus the miR‐155‐5p inhibitor + OGD/R group (P < 0.05), but decreased in the miR‐155‐5p inhibitor + shNEDD4 + shCypD + OGD/R group than in the miR‐155‐5p inhibitor + shNEDD4 + OGD/R group (P < 0.05). Conclusions miR‐155‐5p in I/R‐Exos may facilitate MIRI by inhibiting CypD ubiquitination via targeting NEDD4.

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