RESUMO
Although dysregulation of mitochondrial dynamics has been linked to cellular senescence, which contributes to advanced age-related disorders, it is unclear how Krüppel-like factor 5 (Klf5), an essential transcriptional factor of cardiovascular remodeling, mediates the link between mitochondrial dynamics and vascular smooth muscle cell (VSMC) senescence. Here, we show that Klf5 down-regulation in VSMCs is correlated with rupture of abdominal aortic aneurysm (AAA), an age-related vascular disease. Mice lacking Klf5 in VSMCs exacerbate vascular senescence and progression of angiotensin II (Ang II)-induced AAA by facilitating reactive oxygen species (ROS) formation. Klf5 knockdown enhances, while Klf5 overexpression suppresses mitochondrial fission. Mechanistically, Klf5 activates eukaryotic translation initiation factor 5a (eIF5a) transcription through binding to the promoter of eIF5a, which in turn preserves mitochondrial integrity by interacting with mitofusin 1 (Mfn1). Accordingly, decreased expression of eIF5a elicited by Klf5 down-regulation leads to mitochondrial fission and excessive ROS production. Inhibition of mitochondrial fission decreases ROS production and VSMC senescence. Our studies provide a potential therapeutic target for age-related vascular disorders.
Assuntos
Aneurisma da Aorta Abdominal/genética , Células Endoteliais/metabolismo , Fatores de Transcrição Kruppel-Like/genética , Mitocôndrias/metabolismo , Fatores de Iniciação de Peptídeos/genética , Proteínas de Ligação a RNA/genética , Idoso , Angiotensina II/genética , Angiotensina II/metabolismo , Angiotensina II/farmacologia , Animais , Aorta/diagnóstico por imagem , Aorta/metabolismo , Aorta/patologia , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Senescência Celular/efeitos dos fármacos , Ecocardiografia , Células Endoteliais/patologia , Feminino , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo , Humanos , Fatores de Transcrição Kruppel-Like/deficiência , Masculino , Camundongos , Camundongos Knockout , Mitocôndrias/patologia , Dinâmica Mitocondrial/efeitos dos fármacos , Fatores de Iniciação de Peptídeos/deficiência , Cultura Primária de Células , Regiões Promotoras Genéticas , Ligação Proteica , Espécies Reativas de Oxigênio/metabolismo , Fator de Iniciação de Tradução Eucariótico 5ARESUMO
We report findings in a 34-year-old female patient who presented with fulminant myocarditis 8 days after receiving the first dose of the ZF2001 RBD-subunit vaccine against coronavirus disease 2019 (COVID-19). Autopsy showed severe interstitial myocarditis, including multiple patchy infiltrations of lymphocytes and monocytes in the myocardium of the left and right ventricular walls associated with myocyte degeneration and necrosis. This report highlights the details of clinical presentations and autopsy findings of myocarditis after ZF2001 (RBD-subunit vaccine) vaccination. The correlation between vaccination and death due to myocarditis is discussed.