Cardiac-derived extracellular vesicles improve mitochondrial function to protect the heart against ischemia/reperfusion injury by delivering ATP5a1.

BACKGROUND: Numerous studies have confirmed the involvement of extracellular vesicles (EVs) in various physiological processes, including cellular death and tissue damage. Recently, we reported that EVs derived from ischemia-reperfusion heart exacerbate cardiac injury. However, the role of EVs from healthy heart tissue (heart-derived EVs, or cEVs) on myocardial ischemia-reperfusion (MI/R) injury remains unclear. RESULTS: Here, we demonstrated that intramyocardial administration of cEVs significantly enhanced cardiac function and reduced cardiac damage in murine MI/R injury models. cEVs treatment effectively inhibited ferroptosis and maintained mitochondrial homeostasis in cardiomyocytes subjected to ischemia-reperfusion injury. Further results revealed that cEVs can transfer ATP5a1 into cardiomyocytes, thereby suppressing mitochondrial ROS production, alleviating mitochondrial damage, and inhibiting cardiomyocyte ferroptosis. Knockdown of ATP5a1 abolished the protective effects of cEVs. Furthermore, we found that the majority of cEVs are derived from cardiomyocytes, and ATP5a1 in cEVs primarily originates from cardiomyocytes of the healthy murine heart. Moreover, we demonstrated that adipose-derived stem cells (ADSC)-derived EVs with ATP5a1 overexpression showed much better efficacy on the therapy of MI/R injury compared to control ADSC-derived EVs. CONCLUSIONS: These findings emphasized the protective role of cEVs in cardiac injury and highlighted the therapeutic potential of targeting ATP5a1 as an important approach for managing myocardial damage induced by MI/R injury.

Ginsenoside Rg1 protects against cigarette smoke-induced airway remodeling by suppressing the TGF-ß1/Smad3 signaling pathway.

Chronic obstructive pulmonary disease (COPD) is a devastating and common respiratory disease characterized by chronic inflammation and progressive airway remodeling. Ginsenoside Rg1 (GRg1), a major active component of Panax ginseng, has been found to possess beneficial properties against acute lung injury and respiratory diseases. However, the effects of GRg1 on airway remodeling in COPD remain unclear. In this study, we aimed to investigate the potential protective effects of GRg1 on airway remodeling induced by cigarette smoke (CS) and the underlying mechanism. A rat model of COPD was established in which the animals were subjected to CS and GRg1 daily for 12 weeks. Subsequently, we evaluated lung function, inflammatory responses, along with airway remodeling and associated signaling factors. GRg1 treatment was found to improve pulmonary function, reduce airway collagen volume fraction, and markedly reduce the expression of IL-6, TNF-α, α-SMA, and collagen I. Moreover, GRg1 treatment decreased the expression of TGF-ß1, TGF-ßR1, and phosphorylated-Smad3. In vitro, pretreatment of MRC5 human lung fibroblasts with GRg1 prior to exposure to cigarette smoke extract (CSE) reversed the cell ultrastructure disorder, decreased the expression of IL-6 and TNF-α, and significantly attenuated transdifferentiation of MRC5 cells by suppressing α-SMA and collagen I expression. Additionally, GRg1 suppressed the TGF-ß1/Smad3 signaling pathway in CSE-stimulated MRC5 cells, whereas Smad3 over-expression abolished the anti-transdifferentiation effect of GRg1. In conclusion, the results of our study demonstrated that GRg1 improves lung function and protects against CS-induced airway remodeling, in part by down-regulating the TGF-ß1/Smad3 signaling pathway.

Predictive Value of Uric Acid Regarding Cardiometabolic Disease in a Community-Dwelling Older Population in Shanghai: A Cohort Study.

Aim: This study aimed to test the predictive power of serum uric acid (UA) levels on new-onset cardiometabolic risk in the Chinese population. Methods: Older people who visited a community health center for a yearly health check (N = 5,000; men: 47%, women: 53%) were enrolled. Participants were followed for 4 years from baseline (median: 48 months), with the endpoints being development of heart failure, atrial fibrillation, diabetes, hypertension, metabolic syndrome, or kidney disease. Results: During follow-up, 342 men (7.4%) and 360 women (8.6%) developed hypertension; 98 men (2.48%) and 135 women (3.06%) developed diabetes; and 175 men (5.04%) and 214 women (4.51%) developed metabolic syndrome. Incident diabetes, hypertension, and metabolic syndrome increased with increased UA levels at baseline (P < 0.001). A multivariate Cox proportional hazards analysis revealed a significant, independent association between the baseline UA level and the onset and future hypertension and/or diabetes in both men and women. However, UA is associated with the development of metabolic syndrome in men, but not in women. Conclusion: UA is an independent predictor of new-onset diabetes and hypertension in both women and men and a predictor of new-onset metabolic syndrome only in men.

The Gut Microbial Metabolite Trimethylamine N-Oxide and Hypertension Risk: A Systematic Review and Dose-Response Meta-analysis.

The gut microbial metabolite trimethylamine N-oxide (TMAO) is increasingly regarded as a novel risk factor for cardiovascular events and mortality. However, little is known about the association between TMAO and hypertension. This meta-analysis was conducted to quantitatively assess the relation between the circulating TMAO concentration and hypertension prevalence. The PubMed, Cochrane Library, and Embase databases were systematically searched up to 17 June 2018. Studies recording the hypertension prevalence in members of a given population and their circulating TMAO concentrations were included. A total of 8 studies with 11,750 individuals and 6176 hypertensive cases were included in the analytic synthesis. Compared with low circulating TMAO concentrations, high TMAO concentrations were correlated with a higher prevalence of hypertension (RR: 1.12; 95% CI: 1.06, 1.17; P < 0.0001; I2 = 64%; P-heterogeneity = 0.007; random-effects model). Consistent results were obtained in all examined subgroups as well as in the sensitivity analysis. The RR for hypertension prevalence increased by 9% per 5-µmol/L increment (RR: 1.09; 95% CI: 1.05, 1.14; P < 0.0001) and 20% per 10-µmol/L increment of circulating TMAO concentration (RR: 1.20; 95% CI: 1.11, 1.30; P < 0.0001) according to the dose-response meta-analysis. To our knowledge, this is the first systematic review and meta-analysis demonstrating a significant positive dose-dependent association between circulating TMAO concentrations and hypertension risk.