Thyroid dysfunction in nonvalvular atrial fibrillation and clinical outcomes.

BACKGROUND: Thyroid dysfunction's effects on those who have been diagnosed with atrial fibrillation have not been well investigated. We looked at how thyroid function among patients with pre-existing atrial fibrillation related to thromboembolic risk and clinical outcomes. METHODS: We gathered the medical information of patients diagnosed with nonvalvular atrial fibrillation (NVAF) between 2016 and 2020 at Dongguan People's Hospital. We then assessed the correlation between thyroid dysfunction and thrombotic risk (CHA2DS2-VASc) as well as the occurrence of clinical composite endpoint (all-cause death, heart failure, systemic embolism and hemorrhage events). RESULTS: Of 1329 patients were admitted, 82.6% were euthyroid, 7.4% had subclinical hyperthyroidism, 4.2% had subclinical hypothyroidism, and 6.7% had low triiodothyronine (T3) syndrome. Lower levels of total triiodothyronine (TT3) were linked to an increased risk of thromboembolism (P < 0.005). During a median follow-up period of 1.84 years, there were 608 clinical composite endpoint occurrences. In the adjusted model, Low T3 syndrome was linked to a higher risk of the clinical composite endpoint (HR, 1.68; 95% CI, 1.20-2.37; P < 0.05) in comparison to euthyroidism. Specifically, low T3 syndrome was linked to a higher risk of heart failure (HR, 1.52; 95%CI, 1.01-2.30; P < 0.05) and all-cause death (HR, 3.34; 95% CI, 1.76-6.36; P < 0.001). CONCLUSION: Low T3 syndrome are linked to an increased risk of heart failure and all-cause death in individuals with NVAF. And Patients with NVAF and low TT3 levels have a higher risk of thromboembolism.

MicroRNA alterations in senescent endothelial progenitor cells induced by remnant-like lipoproteins.

BACKGROUND: Remnant-like lipoproteins (RLPs) have been demonstrated to accelerate the onset of endothelial progenitor cells (EPCs) senescence. Recent study has determined that microRNAs (miRNAs) were closely associated with cellular proliferation and senescence. This study aimed to examine whether RLPs lead to an alteration of miRNAs in senescent EPCs. METHODS: RLPs were prepared from plasma samples with immunoaffinity method. After 8 days of culture, EPCs were identified by flow cytometry analysis. Cells were incubated with RLPs for 72 hours. The senescent markers p16INK4a and senescence-associated beta-galactosidase (SA-ß-gal) were detected by Western blotting analysis and ß-gal staining assay, respectively. A human miRNA microarray containing 723 miRNAs was used to detect the expression profile of miRNAs in control and senescent EPCs. The result from the above microarray was qualified by RT-PCR assay. RESULTS: RLPs dose-dependently up-regulated the protein level of p16(INK4a) in EPCs, and RLPs at a concentration of 100 µg/ml induced a significant increase in the percentage of SA-ß-gal-positive EPCs. Of 723 miRNAs, four miRNAs expressed differentially and significantly in RLPs-treated EPCs (P < 0.05), then their changes in expression were validated by real-time RT-PCR. Among them miR-148b and miR-155 were upregulated while miR-574-3p was down-regulated significantly when compared with control (P < 0.01). CONCLUSIONS: RLPs result in the onset of EPCs senescence. Senescent EPCs induced by RLPs exhibit a different profile of miRNAs. These three miR-148b and miR-155 and miR-574-3p reach a significant difference when compared with control, indicating that microRNA might take part in RLPs-induced EPCs senescence.

Remnant-like lipoproteins may accelerate endothelial progenitor cells senescence through inhibiting telomerase activity via the reactive oxygen species-dependent pathway.

BACKGROUND: We previously found that remnant-like lipoproteins (RLPs), lipolytic products of triglyceride-rich lipoproteins including very low-density lipoprotein and chylomicron, can accelerate endothelial progenitor cell (EPC) senescence, which involves telomerase activity. The aim of this study was to investigate the effects of RLPs on telomerase activity and the catalytic subunit telomerase reverse transcriptase (TERT) in EPCs and the associated signal pathway. METHODS: RLPs were prepared from plasma samples by the immunoaffinity method. EPCs at day 8 were incubated with RLPs at 10-, 50-, 100-, and 200-µg/mL for 24 hours. Telomerase activity was measured with telomeric repeat amplification protocol assay, and optimum concentration of RLPs was determined. Human TERT (hTERT) and phosphorylated Akt protein kinase were detected by Western blot analysis in RLP-incubated EPCs with or without pretreatment of either superoxide dismutase or atorvastatin for 3 hours. Phosphorylated hTERT was measured by immunoprecipitation and Western blot assay. Nitrotyrosine was evaluated by immunofluorescence assay, and senescent EPCs were determined by senescence-associated ß-galactosidase staining. RESULTS: Dose dependently, RLPs resulted in a decrease in telomerase activity, with a maximal effect at 200 µg protein/mL. The optimum concentration of RLPs was determined as 100 µg protein/mL. This dosage resulted in significant increases in senescence-associated ß-galactosidase-positive cell and nitrotyrosine staining. In addition, RLPs decreased the expression of hTERT and repressed the phosphorylation of Akt and hTERT. Pretreatment of either superoxide dismutase or atorvastatin remarkably reversed these effects. CONCLUSIONS: RLPs may suppress telomerase activity and accelerate EPC senescence through downregulating hTERT expression via the reactive oxygen species-dependent pathway.

Interaction between remnant-like lipoprotein particles and adipocytes.

Inflammation plays a pivotal role in the pathophysiology of atherosclerosis. Remnant-like lipoprotein particles (RLPs) have been implicated as potentially atherogenic lipoproteins. RLPs can induce a pronounced inflammatory response especially during the postprandial phase. Increasing evidence demonstrates that adipose tissue may be a significant contributor to the increased systemic inflammation through secretion of various proinflammatory adipocytokines. In addition, adipocytes may potentially regulate RLPs metabolism. Therefore, we hypothesized that there might be an interaction between RLPs and adipocytes.

Remnant-like particles accelerate endothelial progenitor cells senescence and induce cellular dysfunction via an oxidative mechanism.

Remnant-like particles (RLPs) are closely associated with coronary heart disease and can induce endothelial dysfunction through oxidative mechanisms. Many risk factors accelerate the onset of endothelial progenitor cells (EPCs) senescence via increased oxidative stress. In this study, we investigated the effect of RLPs on EPCs senescence and function. RLPs were isolated from postprandial plasma of hypertriglyceridemic patients by use of the immunoaffinity gel mixture of anti-apoA-1 and anti-apoB-100 monoclonal antibodies. Our results show that EPCs became senescent as determined by senescence-associated acidic beta-galactosidase (SA-beta-Gal) staining after ex vivo cultivation without any stimulation. Co-incubation with RLPs accelerated the increase in SA-beta-Gal-positive EPCs. The acceleration of RLPs-induced EPCs senescence occurred dose-dependently with a maximal effect when EPCs were treated with RLPs at 0.10 mg cholesterol/mL (P<0.01). Moreover, RLPs decreased adhesion, migration and proliferation capacities of EPCs as assessed by adherence to fibronectin, modified Boyden chamber technique and MTT assay (P<0.01), respectively. RLPs increased nitrotyrosine staining in EPCs. However, RLPs-induced EPCs senescence and dysfunction were significantly inhibited by pre-treatment of superoxide dismutase (50 U/mL) (P<0.05). Our results provide evidence that RLPs accelerate the onset of EPC senescence via increased oxidative stress, accompanying with the impairment of adhesion, migration and proliferation capacities.

Cyclin-dependent kinase inhibitor p16(INK4a) and telomerase may co-modulate endothelial progenitor cells senescence.

Endothelial cells (ECs) damage is an initial and pivotal step in the formation of atherosclerosis. Endothelial progenitor cells (EPCs), which have been considered as the precursor of ECs, can migrate and home to the site of injured ECs to divide into mature ECs and keep the integrity of the endothelial monolayer. It has been shown that the number and function of EPCs are negatively correlated with various atherosclerotic risk factors. This finding may be explained partly by accelerated senescence of EPCs induced by telomere attrition or shortening owning to oxidative stress and accumulative ROS. However, elevated telomerase activity which extends the telomere cannot lead to cellular immortal in the presence of the cyclin-dependent kinase inhibitor p16(INK4a). Researchers have the opinion that senescence is the balance between the regeneration and cancer. High expression of phosphorylated p16(INK4a), which is caused by oxidative stress and accumulative ROS, can prevent tumor cells from unlimited division and becoming malignant ones by accelerating premalignant cells premature senescence. It has been demonstrated that the expression of p16(INK4a) increases remarkably with age due to oxidative stress and accumulative ROS in some stem and progenitor cells, and regulates these cells age-dependent senescence. It is observed that telomeres shortening exists in these cells. Therefore, it can be hypothesized that p16(INK4a), together with telomerase, may co-modulate EPCs senescence.