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

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.

Identification of potential miR‑155 target genes in epidermal immune microenvironment of atopic dermatitis patients and their inflammatory effects on HaCaT cells

“…In monocytes/macrophages, miR-155 has been reported to regulate inflammatory responses that are activated by certain cytokines (such as TNFα, IL-1β) or Toll-like receptor ligands in various cell types ( 18 , 20 ). In addition, miR-155 can promote M1 macrophage polarization, leading to local inflammation in the heart and even systemic inflammation in distant organs ( 21 ). miR-155 expression was found to be significantly increased in skin lesions of patients with AD ( 10 ).…”

Unraveling the Signaling Dynamics of Small Extracellular Vesicles in Cardiac Diseases

“…Guo et al (2021) reveal that, in addition to differential expression in exosomal miRNAs identifying up to 18 miRNAs as biomarkers, exosomes differ in size, being smaller in MI patients [69] (Table 1). Some miRNAs have been widely studied due to their essential role in post-MI inflammatory, fibrotic and angiogenic processes, i.e., miR-126 or miR-155, which are upregulated in exosomes of MI patients, and miR-21 or miR-146a-5p, which are downregulated [71][72][73]. Specifically, miR-146a-5p is associated with inflammation after MI by regulating M1 macrophage polarization through the regulation of TNF Receptor-Associated Factor Some miRNAs have been widely studied due to their essential role in post-MI inflammatory, fibrotic and angiogenic processes, i.e., miR-126 or miR-155, which are upregulated in exosomes of MI patients, and miR-21 or miR-146a-5p, which are downregulated [71][72][73].…”

Cardiac microRNAs: diagnostic and therapeutic potential

“…After myocardial damage, the loss of cardiomyocytes is mostly irreversible, which results in scar formation and cardiac remodeling [ 53 , 71 , 72 ]. In this process, microRNAs can influence cardiac hypertrophy [ 54 ], especially by modulating glucose-6-phosphate dehydrogenase or pentose phosphate pathways, by stimulating cardiac cell apoptosis and subsequent fibrosis [ 53 ], or by modifying myofibroblast density [ 55 , 56 ]. Tracing different cell lines and their potential to survive and regenerate after myocardial injury is the main issue of many current studies, as it can result in establishing genes or their target proteins as potential therapeutic points.…”