Jiawen Liang

Accumulating evidence has shown that endothelial progenitor cell‐derived exosomes (EPC‐Exos) can ameliorate myocardial fibrosis. The purpose of the present study was to investigate the effects of EPC‐Exos‐derived microRNAs (miRNAs) on myocardial infarction (MI). A miRNA‐Seq dataset of miRNAs differentially expressed between EPCs and exosomes was collected. Quantitative real‐time polymerase chain reaction (qRT‐PCR) was used to validate the miRNA expression indicated by miRNA‐Seq. Immunofluorescence, cell proliferation, and angiogenesis assays were employed to investigate the effects of miRNAs on cardiac fibroblasts (CFs) in vitro. Interactions between miRNAs and their respective targets were examined via immunoblotting, qRT‐PCR, and luciferase reporter assays. An MI rat model was constructed, and various staining and immunohistochemical assays were performed to explore the mechanisms underlying the miRNA‐mediated effects on MI. miR‐363‐3p and miR‐218‐5p were enriched in EPC‐Exos, and miR‐218‐5p and miR‐363‐3p mimic or inhibitor enhanced or suppressed CF proliferation and angiogenesis, respectively. miR‐218‐5p and miR‐363‐3p regulated p53 and junction‐mediating and regulatory protein (JMY) by binding to the promoter region of p53 and the 3 ^′ untranslated region of JMY. Additionally, treatment of CFs with Exo‐miR‐218‐5p or Exo‐miR‐363‐3p upregulated p53 and downregulated JMY expression, promoted mesenchymal‐endothelial transition, and inhibited myocardial fibrosis. Administration of exosomes containing miR‐218‐5p mimic or miR‐363‐3p mimic ameliorated left coronary artery ligation‐induced MI and restored myocardial tissue integrity in the MI model rats. In summary, these results show that the protective ability of EPC‐Exos against MI was mediated by the shuttled miR‐218‐5p or miR‐363‐3p via targeting of the p53/JMY signaling pathway.

Hyperlipidemia is an important factor in the induction of cardiovascular diseases. However, the molecular mechanisms underlying the vascular injury involved in hyperlipidemia remains unclear. This study aimed to investigate the Notch pathway of endothelial progenitor cells (EPCs) in reendothelialization after vascular injury and to explore the involvement of Notch pathway in the senescence of EPCs. Our results demonstrated that high-fat diet (HFD) treatment inhibited reendothelialization after vascular injury in the mice model. In vitro studies showed that 7-ketocholesterol (7-keto) stimulation induced senescence in the isolated EPCs from mice. In addition, 7-keto markedly upregulated the protein expression of Notch1 and Delta-like ligand 4 and induced the transport of notch intracellular domain (NICD) to the nucleus. Mechanistically, treatment with NICD inhibitor reduced the senescence of the EPCs stimulated by cholesterol. In summary, our results showed that HFD treatment caused the disruption of reendothelialization after vascular injury in the mouse model. In vitro studies indicated that 7-keto-induced senescence of EPCs was at least via the activation of the Notch1 pathway. Mechanistic data suggested that 7-keto may activate the Notch1 pathway by regulating the generation and transport of NICD to the nucleus. Future investigations are warranted to confirm the role of Notch1 in the dysfunction of EPCs during obesity.

To evaluate association of 24 h–systolic blood pressure (SBP) variability and obstructive sleep apnea (OSA) as defined by the apnea-hypopnea index ≥5/h; and association of 24 h–SBP variability and prevalent cardiovascular disease (CVD) in OSA patients. Participants underwent polysomongraphy to evaluate the presence of OSA, and 24 h–ambulatory blood pressure monitoring was applied to evaluate 24 h–SBP variability as indexed by weighted 24 h–standard deviation (SD) of SBP. Between-group differences were evaluated in participants with and without OSA. Participants with OSA were divided into high and low 24 h–SBP variability groups and between-group differences were evaluated. Mean age of 384 participants was 50 years old and 42.2% had OSA. Mean 24 h–systolic/diastolic BP were 130/78 mmHg, with mean weighted 24 h–SD of systolic/diastolic BP were 12.9/7.3 mmHg. Compared to those without OSA, OSA participants had higher clinic-, 24 h-, daytime- and nighttime-SBP, and weighted 24 h, daytime- and nighttime-SD of SBP. Age, prevalent CVD and OSA, usage of angiotensin converting enzyme inhibitor/angiotensin receptor blocker, calcium channel blocker and diuretic were significantly associated with 24 h–SBP variability. In OSA patients, compared to those with low variability, participants with high variability had higher weighted 24 h, daytime- and nighttime-SD of SBP. After adjusted for covariates including clinic-SBP and 24 h–SBP, per 1-SD increment weighted 24 h–SD of SBP was associated with 21% increased prevalent CVD. Patients with newly-diagnosed OSA have higher 24 h–SBP variability compared to those without OSA; in OSA patients, increased 24 h–SBP variability is associated with increased prevalence of CVD.