An ERK5-NRF2 Axis Mediates Senescence-Associated Stemness and Atherosclerosis.

BACKGROUND: ERK5 (extracellular signal-regulated kinase 5) is a dual kinase transcription factor containing an N-terminal kinase domain and a C-terminal transcriptional activation domain. Many ERK5 kinase inhibitors have been developed and tested to treat cancer and inflammatory diseases. However, recent data have raised questions about the role of the catalytic activity of ERK5 in proliferation and inflammation. We aimed to investigate how ERK5 reprograms myeloid cells to the proinflammatory senescent phenotype, subsequently leading to atherosclerosis. METHODS: A ERK5 S496A (dephosphorylation mimic) knock in (KI) mouse model was generated using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9), and atherosclerosis was characterized by hypercholesterolemia induction. The plaque phenotyping in homozygous ERK5 S496A KI and wild type (WT) mice was studied using imaging mass cytometry. Bone marrow-derived macrophages were isolated from hypercholesterolemic mice and characterized using RNA sequencing and functional in vitro approaches, including senescence, mitochondria reactive oxygen species, and inflammation assays, as well as by metabolic extracellular flux analysis. RESULTS: We show that atherosclerosis was inhibited in ERK5 S496A KI mice. Furthermore, ERK5 S496 phosphorylation mediates both senescence-associated secretory phenotype and senescence-associated stemness by upregulating AHR (aryl hydrocarbon receptor) in plaque and bone marrow-derived macrophages isolated from hypercholesterolemic mice. We also discovered that ERK5 S496 phosphorylation could induce NRF2 (NFE2-related factor 2) SUMOylation at a novel K518 site to inhibit NRF2 transcriptional activity without altering ERK5 catalytic activity and mediates oxidized LDL (low-density lipoprotein)-induced senescence-associated secretory phenotype. Specific ERK5 kinase inhibitors (AX15836 and XMD8-92) also inhibited ERK5 S496 phosphorylation, suggesting the involvement of ERK5 S496 phosphorylation in the anti-inflammatory effects of these ERK5 kinase inhibitors. CONCLUSIONS: We discovered a novel mechanism by which the macrophage ERK5-NRF2 axis develops a unique senescence-associated secretory phenotype/stemness phenotype by upregulating AHR to engender atherogenesis. The finding of senescence-associated stemness phenotype provides a molecular explanation to resolve the paradox of senescence in proliferative plaque by permitting myeloid cells to escape the senescence-induced cell cycle arrest during atherosclerosis formation.

Nkx2-5 Loss of Function in the His-Purkinje System Hampers Its Maturation and Leads to Mechanical Dysfunction.

The ventricular conduction or His-Purkinje system (VCS) mediates the rapid propagation and precise delivery of electrical activity essential for the synchronization of heartbeats. Mutations in the transcription factor Nkx2-5 have been implicated in a high prevalence of developing ventricular conduction defects or arrhythmias with age. Nkx2-5 heterozygous mutant mice reproduce human phenotypes associated with a hypoplastic His-Purkinje system resulting from defective patterning of the Purkinje fiber network during development. Here, we investigated the role of Nkx2-5 in the mature VCS and the consequences of its loss on cardiac function. Neonatal deletion of Nkx2-5 in the VCS using a Cx40-CreERT2 mouse line provoked apical hypoplasia and maturation defects of the Purkinje fiber network. Genetic tracing analysis demonstrated that neonatal Cx40-positive cells fail to maintain a conductive phenotype after Nkx2-5 deletion. Moreover, we observed a progressive loss of expression of fast-conduction markers in persistent Purkinje fibers. Consequently, Nkx2-5-deleted mice developed conduction defects with progressively reduced QRS amplitude and RSR' complex associated with higher duration. Cardiac function recorded by MRI revealed a reduction in the ejection fraction in the absence of morphological changes. With age, these mice develop a ventricular diastolic dysfunction associated with dyssynchrony and wall-motion abnormalities without indication of fibrosis. These results highlight the requirement of postnatal expression of Nkx2-5 in the maturation and maintenance of a functional Purkinje fiber network to preserve contraction synchrony and cardiac function.

Post-traumatic stress disorder, anxiety, depression and related factors among COVID-19 patients during the fourth wave of the pandemic in Vietnam.

BACKGROUND: This study investigated post-traumatic stress disorder (PTSD), anxiety, depression and their related factors among coronavirus disease 2019 (COVID-19) patients during the fourth wave of the pandemic in Vietnam. METHODS: Vietnamese-fluent confirmed COVID-19 patients for at least 3 d were recruited in this online cross-sectional study to answer a three-part questionnaire including participants' sociodemographic characteristics, PTSD (Impact of Event Scale-Revised) and anxiety and depression (Hospital Anxiety and Depression Scale). Associated factors were determined using multivariable binary logistic regression models. RESULTS: Of 1544 responses, the majority were female (53.0%), ages 18-39 y (74.8%) and were isolated and treated at field hospitals (72.2%). Family or friends were the greatest sources of mental support (68.2%), followed by healthcare providers (51.1%). The overall prevalence rates of PTSD, anxiety and depression among COVID-19 patients were 22.9%, 11.2% and 17.4%, respectively. Risk factors included older age, higher education, getting infected from the public, knowing someone who died from COVID-19 and high perception of life threat. Meanwhile, mental assistance from family or friends, a greater number of supporters, living with someone not vulnerable and higher salaries were significantly protective factors. CONCLUSIONS: The psychological responses associated with some sociodemographic details. Family or friends should be the first line of mental interventions for COVID-19 patients.

Knowledge, Attitudes, Practices, and Related Factors Towards COVID-19 Prevention Among Patients at University Medical Center Ho Chi Minh City, Vietnam.

AIM: This study measured the level of knowledge, attitudes and practices towards COVID-19 prevention and examined associated factors among patients at a national tertiary general hospital in Vietnam. METHODS: Adult patients admitted to University Medical Center during research period were recruited in a cross-sectional study, which employed a convenience sampling method with a 4-component questionnaire in order to examine the patients' consciousness towards COVID-19 spreading prevention based on four aspects: demographic characteristics (10 items), knowledge (14 items), attitudes (6 items), and practices (7 items). RESULTS: The study involved 2769 respondents (18-90 years) with the mean age of 38.05±13.91 years. About two thirds of the respondents obtained diploma degree or higher (63.4%) and shared their living space with others (64.4%). The majority of patients settled in urban area (74.9%). All participants stayed informed about COVID-19, with the most commonly used channels like television (75.2%), the Internet (72.2%) and phone (69.8%). The vast majority showed sufficient knowledge (93.7%) and positive attitudes (76.3%). Just over half of participants remained good practiced of COVID-19 prevention (57.7%). On average, the factors of younger age, higher educational level, frequency and department of admission, and the number of COVID-19 informative channels were significantly associated with sufficient knowledge, positive attitudes, and good practices regarding preventive action against COVID-19 spreading. The optimistic attitude and having more undergoing chronic diseases were associated with the likelihood of well-practiced COVID-19 preventive measures (OR 3.63, 95% CI 1.54-8.55, p=0.003 and OR 0.86, 95% CI 0.78-0.98, p=0.02, respectively). CONCLUSION: The results of this study demonstrated that the likelihood of good preventive practices in the fight against COVID-19 pandemic was influenced by attitudes and several sociodemographic factors. More drastic interventions for the prevention of COVID-19 should be widely furnished and equipped in hospitals, through various routes to maximize the efficiency and adherence to prevention practices.

Correction: Deletion of Nkx2-5 in trabecular myocardium reveals the developmental origins of pathological heterogeneity associated with ventricular non-compaction cardiomyopathy.

[This corrects the article DOI: 10.1371/journal.pgen.1007502.].

Deletion of Nkx2-5 in trabecular myocardium reveals the developmental origins of pathological heterogeneity associated with ventricular non-compaction cardiomyopathy.

Left ventricular non-compaction (LVNC) is a rare cardiomyopathy associated with a hypertrabeculated phenotype and a large spectrum of symptoms. It is still unclear whether LVNC results from a defect of ventricular trabeculae development and the mechanistic basis that underlies the varying severity of this pathology is unknown. To investigate these issues, we inactivated the cardiac transcription factor Nkx2-5 in trabecular myocardium at different stages of trabecular morphogenesis using an inducible Cx40-creERT2 allele. Conditional deletion of Nkx2-5 at embryonic stages, during trabecular formation, provokes a severe hypertrabeculated phenotype associated with subendocardial fibrosis and Purkinje fiber hypoplasia. A milder phenotype was observed after Nkx2-5 deletion at fetal stages, during trabecular compaction. A longitudinal study of cardiac function in adult Nkx2-5 conditional mutant mice demonstrates that excessive trabeculation is associated with complex ventricular conduction defects, progressively leading to strain defects, and, in 50% of mutant mice, to heart failure. Progressive impaired cardiac function correlates with conduction and strain defects independently of the degree of hypertrabeculation. Transcriptomic analysis of molecular pathways reflects myocardial remodeling with a larger number of differentially expressed genes in the severe versus mild phenotype and identifies Six1 as being upregulated in hypertrabeculated hearts. Our results provide insights into the etiology of LVNC and link its pathogenicity with compromised trabecular development including compaction defects and ventricular conduction system hypoplasia.