Atorvastatin treatment ameliorates cardiac function and remodeling induced by isoproterenol attack through mitigation of ferroptosis.

Ferroptosis has been identified as an important role in damaged heart. Meanwhile, statin therapy has been reported to be beneficial for the treatment of heart failure(HF) under different conditions. However, the beneficial effects of statin treatment on regulation of ferroptosis in failing heart is unveiled. The aim of this study is to explore the protective efficacy of atorvastatin against the ferroptosis related signaling pathway in isoproterenol(ISO)-induced HF. We found that ATV and ferrostatin-1(Fer-1,as a positive control) significantly improved ISO-decreased cell viability and cell survival by reducing oxidative stress and Fe2+-dependent lipid peroxidation in H9C2 cells. Additionally, ISO triggered marked ferritinophagy accompanied by up-regulating protein levels of LC3BII,NCOA4 and Beclin1 and down-regulating protein levels of P62 and FTH1 in damaged cells, which nevertheless was significantly blocked by administration of ATV and these results were in parallel with the results obtained after 3-methyadenine(3-MA) treatment. Consistently, C57BL/6J mice were used in used in this study and administered 5 mg/kg/day ISO for 2 weeks to simulate cardiac injury. 20 mg/kg/day ATV treatment for 2 weeks simultaneously markedly improved cardiac dysfunction and remodeling induced by ISO attack. ATV showed significantly protective effects through suppressing the activation of ferroptosis related signaling, as evidenced by decreasing the mRNA levels of PTGS2(a marker of ferroptosis), contents of malonaldehyde and protein levels of NOX4 and increasing the contents of glutathione(GSH), the ratio of GSH/GSSG and protein levels of GPX4 and SLC7A11. Moreover, ISO evidently triggered degradation of FTH1 in failing heart. However, ATV significantly prevented these changes in damaged heart. Overall, these results reveal atorvastatin suppresses ferroptosis and exhibits protective effect on failing myocardium of mice after ISO insult though inhibiting ferritinophagy-mediated ferroptosis, which might be a potential therapeutic strategy in the prevention of ISO-associated cardiomyopathy.

Exploring the causal role of gut microbiota in giant cell arteritis: a Mendelian randomization analysis with mediator insights.

Background: Giant Cell Arteritis (GCA) is a complex autoimmune condition. With growing interest in the role of gut microbiota in autoimmune diseases, this research aimed to explore the potential causal relationship between gut microbiota and GCA, and the mediating effects of specific intermediaries. Methods: Using a bidirectional two-sample Mendelian randomization (MR) design, we investigated associations between 191 microbial taxa and GCA. A two-step MR technique discerned the significant mediators on this relationship, followed by Multivariable MR analyses to quantify the direct influence of gut microbiota on GCA and mediation effect proportion, adjusting for these mediators. Results: Nine taxa displayed significant associations with GCA. Among them, families like Bacteroidales and Clostridiaceae1 had Odds Ratios (OR) of 1.48 (p=0.043) and 0.52 (p=5.51e-3), respectively. Genera like Clostridium sensu stricto1 and Desulfovibrio showed ORs of 0.48 (p=5.39e-4) and 1.48 (p=0.037), respectively. Mediation analyses identified 25 hydroxyvitamin D level (mediation effect of 19.95%), CD14+ CD16- monocyte counts (mediation effect of 27.40%), and CD4+ T cell counts (mediation effect of 28.51%) as significant intermediaries. Conclusion: Our findings provide invaluable insights into the complex interplay between specific gut microbiota taxa and GCA. By highlighting the central role of gut microbiota in influencing GCA risk and long-term recurrence, and their interactions with vital immune mediators, this research paves the way for potential therapeutic interventions in GCA management.