Myo1b Promotes Premature Endothelial Senescence and Dysfunction via Suppressing Autophagy: Implications for Vascular Aging.
Yi YuYuanyuan RenZi LiYang LiYirong LiYan ZhangRunlin GuiYue CuiLu QianYuyan XiongPublished in: Oxidative medicine and cellular longevity (2023)
Endothelial cell (EC) senescence characterized by an irreversible growth arrest leading to endothelial dysfunction has been implicated in vascular aging and aging-associated cardiovascular diseases. Autophagy plays a crucial role in the modulation of cellular senescence. Our previous showed that myosin 1b (Myo1b), one family of nonfilamentous class-1 myosin, was reported to be involved in the modulation of human smooth muscle cell senescence. However, the role of Myo1b in the modulation of EC senescence with links to autophagy has yet to be elucidated. In this study, we sought to explore the role of Myo1b in endothelial senescence and further elucidate the underlying mechanisms. Here, we show prominent upregulation of Myo1b in senescent ECs in comparison with nonsenescence ECs in both mRNA and protein expression levels. Silencing Myo1b in senescent cells ameliorates endothelial dysfunctions and reverses endothelial senescence phenotypic changes such as senescence-associated- β -galactosidase activity, cyclin-dependent kinase inhibitor p21 WAF1 , expression of vascular adhesion molecule-1 (VCAM1) and intercellular adhesion molecule-1 (ICAM1), and the senescence-associated cytokines. In contrast, in nonsenescent cells, overexpressing Myo1b promotes endothelial senescence and suppresses autophagy through the impairment of autophagosome and lysosome fusion. The interaction between Myo1b and LRRK2 through Myo1b tail domain promotes intracellular calcium elevation, which results in the inhibition of autophagic flux. In vitro and in vivo aging models, Myo1b knockdown in senescent ECs and wild type-aged mice is able to enhance autophagy and ameliorate aging-associated endothelial dysfunction. Taken together, our studies reveal a new function for Myo1b, that is, to couple LRRK2 assembly to promote an increase in intracellular calcium level, which impairs the autophagosome-lysosome fusion, and ultimately the promotion of EC senescence and vascular aging.
Keyphrases
- endothelial cells
- dna damage
- cell death
- high glucose
- signaling pathway
- induced apoptosis
- endoplasmic reticulum stress
- stress induced
- oxidative stress
- vascular endothelial growth factor
- cell cycle arrest
- binding protein
- cardiovascular disease
- magnetic resonance imaging
- poor prognosis
- wild type
- escherichia coli
- magnetic resonance
- staphylococcus aureus
- type diabetes
- cell proliferation
- single cell
- cell cycle
- genome wide
- mesenchymal stem cells
- skeletal muscle
- bone marrow
- cell therapy
- long non coding rna
- cell adhesion
- induced pluripotent stem cells
- case control