ACE2‐EPC‐EXs protect ageing ECs against hypoxia/reoxygenation‐induced injury through the miR‐18a/Nox2/ROS pathway

Abstract

Oxidative stress is one of the mechanisms of ageing‐associated vascular dysfunction. Angiotensin‐converting enzyme 2 (ACE2) and microRNA (miR)‐18a have shown to be down‐regulated in ageing cells. Our previous study has shown that ACE2‐primed endothelial progenitor cells (ACE2‐EPCs) have protective effects on endothelial cells (ECs), which might be due to their released exosomes (EXs). Here, we aimed to investigate whether ACE2‐EPC‐EXs could attenuate hypoxia/reoxygenation (H/R)‐induced injury in ageing ECs through their carried miR‐18a. Young and angiotensin II‐induced ageing ECs were subjected to H/R and co‐cultured with vehicle (medium), EPC‐EXs, ACE2‐EPCs‐EXs, ACE2‐EPCs‐EXs + DX600 or ACE2‐EPCs‐EXs with miR‐18a deficiency (ACE2‐EPCs‐EXsanti‐miR‐18a). Results showed (1) ageing ECs displayed increased senescence, apoptosis and ROS production, but decreased ACE2 and miR‐18a expressions and tube formation ability; (2) under H/R condition, ageing ECs showed higher rate of apoptosis, ROS overproduction and nitric oxide reduction, up‐regulation of Nox2, down‐regulation of ACE2, miR‐18a and eNOS, and compromised tube formation ability; (3) compared with EPC‐EXs, ACE2‐EPC‐EXs had better efficiencies on protecting ECs from H/R‐induced changes; (4) The protective effects were less seen in ACE2‐EPCs‐EXs + DX600 and ACE2‐EPCs‐EXsanti‐miR‐18a groups. These data suggest that ACE‐EPCs‐EXs have better protective effects on H/R injury in ageing ECs which could be through their carried miR‐18a and subsequently down‐regulating the Nox2/ROS pathway.

Impact of the Renin–Angiotensin System on the Endothelium in Vascular Dementia: Unresolved Issues and Future Perspectives

“…Arterial and venous endothelial cells express angiotensin-converting enzyme 2 (ACE2), which is now suggested to protect against ischemia-induced cerebral injuries. When exosomes of endothelial progenitor cells are transfected with lentivirus containing human ACE2 cDNA (ACE2-EPC-EXs), a protective effect on hypoxia/reoxygenation (H/R)-induced injury in cultured aging brain endothelial cells emerges [ 49 ]. However, only a partial protection is observed with ACE2-EPC-EXs anti-miR-18a , suggestive of miR-18a involvement.…”

“…However, only a partial protection is observed with ACE2-EPC-EXs anti-miR-18a , suggestive of miR-18a involvement. Subsequent analysis revealed that the observed protection is mediated through anti-apoptotic and anti-oxidative effects via the miR-18a/Nox2/ROS pathway [ 49 ]. In a more recent study, ACE2-EPC-exosomes were shown to protect cerebral microvascular endothelial cells with Ang II-induced injury against apoptosis, ROS generation, mitochondrion fragmentation, and reduced tube formation and migration abilities.…”

Macrophage migration inhibitory factor serves a pivotal role in�the regulation of radiation-induced cardiac senescencethrough rebalancing the microRNA-34a/sirtuin 1 signaling pathway

“…Cellular senescence is defined as the stable cell cycle arrest elicited in response to a variety of stressors (37). The accumulation of oxidative stress in cardiomyocytes has been reported to cause senescence and reduce cardiac function (18). Radiation-associated oxidative stress and telomere loss have all been linked to the induction of the senescent phenotype through replication stress-induced DNA damage (38,39).…”

“…Oxidative stress is an important inducer of cardiomyocyte senescence (18), with radiation being a major cause of reactive oxygen species (ROS) production (19). Upregulation of antioxidant proteins, such as endothelial nitric oxide synthase (eNOS) and catalase, has been demonstrated to protect against oxidative stress-mediated senescence (20).…”

Noncoding RNAs in Vascular Aging

“…Another study found that miR-18a expression was decreased in aging ECs and miR-18a protects ECs from hypoxia/reoxygenation-induced injury by downregulating the Nox2/ROS pathway [74]. In addition, some components of the miR-17-92 cluster (miR-18a, miR-17-5p, and miR-20a) may participate in the control of angiogenic phenotypes such as the proliferation, survival, [75]. Further, miR-214, which is highly expressed in ECs, is enriched in EC-derived exosomes; senescent cells with reduced miR-214 levels can be rescued by absorbing exosomal miR-214 produced by neighboring cells.…”