Smooth muscle SIRT1 reprograms endothelial cells to suppress angiogenesis after ischemia

Dou, Yong-Qing; Kong, Pengfei; Li, Changlin; Sun, Hongmin; Li, Weiwei; Yuan, Yu; Nie, Lei; Zhao, Lili; Miao, Sui-Bing; Li, Xiaokun; Dong, Chen; Jin-wen, Zhang; Liu, Yang; Huo, Xiaoxia; Chi, Kui; Gao, Xiang; Zhang, Ning; Weng, Lin; Yang, Hongyuan; Zhang, Fan; Han, Mei Lan K.

doi:10.7150/thno.39320

Cited by 52 publications

(34 citation statements)

References 44 publications

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“…SIRT1 has been shown to be a key regulator of vascular endothelial homeostasis, improving angiogenesis 22 , 35 , preventing renal dysfunction, and attenuating nephrosclerosis 36 . Therefore, we examined SIRT1 after AMSC-derived exosome treatment.…”

Section: Resultsmentioning

confidence: 99%

Exosomes derived from GDNF-modified human adipose mesenchymal stem cells ameliorate peritubular capillary loss in tubulointerstitial fibrosis by activating the SIRT1/eNOS signaling pathway

Chen

Wang

et al. 2020

Theranostics

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Mesenchymal stem cells (MSCs) have emerged as ideal cell-based therapeutic candidates for the structural and functional restoration of the diseased kidney. Glial cell line-derived neurotrophic factor (GDNF) has been demonstrated to promote the therapeutic effect of MSCs on ameliorating renal injury. The mechanism may involve the transfer of endogenous molecules via paracrine factors to salvage injured cells, but these factors remain unknown. Methods: GDNF was transfected into human adipose mesenchymal stem cells via a lentiviral transfection system, and exosomes were isolated (GDNF-AMSC-exos). Using the unilateral ureteral obstruction (UUO) mouse model and human umbilical vein endothelial cells (HUVECs) against hypoxia/serum deprivation (H/SD) injury models, we investigated whether GDNF-AMSC-exos ameliorate peritubular capillary (PTC) loss in tubulointerstitial fibrosis and whether this effect is mediated by the Sirtuin 1 (SIRT1) signaling pathway. Additionally, by using SIRT1 activators or siRNAs, the roles of the candidate mRNA and its downstream gene in GDNF-AMSC-exo-induced regulation of endothelial cell function were assessed. PTC characteristics were detected by fluorescent microangiography (FMA) and analyzed by the MATLAB software. Results: The green fluorescent PKH67-labeled exosomes were visualized in the UUO kidneys and colocalized with CD81. GDNF-AMSC-exos significantly decreased PTC rarefaction and renal fibrosis scores in mice with UUO. In vitro studies revealed that GDNF-AMSC-exos exerted cytoprotective effects on HUVECs against H/SD injury by stimulating migration and angiogenesis as well as conferring apoptosis resistance. Mechanistically, GDNF-AMSC-exos enhanced SIRT1 signaling, which was accompanied by increased levels of phosphorylated endothelial nitric oxide synthase (p-eNOS). We also confirmed the SIRT1-eNOS interaction in HUVECs by immunoprecipitation. Furthermore, we observed a correlation of the PTC number with the SIRT1 expression level in the kidney in vivo . Conclusion: Our study unveiled a mechanism by which exosomes ameliorate renal fibrosis: GDNF-AMSC-exos may activate an angiogenesis program in surviving PTCs after injury by activating the SIRT1/eNOS signaling pathway.

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Section: Resultsmentioning

confidence: 99%

Exosomes derived from GDNF-modified human adipose mesenchymal stem cells ameliorate peritubular capillary loss in tubulointerstitial fibrosis by activating the SIRT1/eNOS signaling pathway

Chen

Wang

et al. 2020

Theranostics

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“…Recent evidence suggests that body fluid EVs are involved in numerous physiological processes and play essential roles in remodeling homeostasis of the body [6] . In particular, plasma EVs originate from host cells mediate their mutual regulation locally or remotely, these EVs have cell type-specific biomolecules and could be exploited as predictive biomarkers for disease treatment [7] , [8] , [9] , [10] , [11] , [12] , [13] , [14] . The brain cell originated EVs could also be detected in CSF reflect the physiological and pathological changes taking place in the originated brain tissue [15] , [16] , [17] .…”

Section: Introductionmentioning

confidence: 99%

EV-origin: Enumerating the tissue-cellular origin of circulating extracellular vesicles using exLR profile

et al. 2020

Computational and Structural Biotechnology Journal

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“…Similarly, circSTAG1 ameliorated astrocyte dysfunction and depressive-like behaviors induced by chronic unpredictable stress by capturing ALKBH5 in the cytoplasm and increasing m6A levels of fatty acid amide hydrolase (FAAH) mRNA [ 139 , 166 ]. CircBACH1 [ 140 ] and circZFP609 [ 141 ] also fall in this situation.…”

Section: Circrna-protein Interactionsmentioning

confidence: 99%

Circular RNA: metabolism, functions and interactions with proteins

et al. 2020

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Circular RNAs (CircRNAs) are single-stranded, covalently closed RNA molecules that are ubiquitous across species ranging from viruses to mammals. Important advances have been made in the biogenesis, regulation, localization, degradation and modification of circRNAs. CircRNAs exert biological functions by acting as transcriptional regulators, microRNA (miR) sponges and protein templates. Moreover, emerging evidence has revealed that a group of circRNAs can serve as protein decoys, scaffolds and recruiters. However, the existing research on circRNA-protein interactions is quite limited. Hence, in this review, we briefly summarize recent progress in the metabolism and functions of circRNAs and elaborately discuss the patterns of circRNA-protein interactions, including altering interactions between proteins, tethering or sequestering proteins, recruiting proteins to chromatin, forming circRNA-protein-mRNA ternary complexes and translocating or redistributing proteins. Many discoveries have revealed that circRNAs have unique expression signatures and play crucial roles in a variety of diseases, enabling them to potentially act as diagnostic biomarkers and therapeutic targets. This review systematically evaluates the roles and mechanisms of circRNAs, with the hope of advancing translational medicine involving circRNAs.

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Smooth muscle SIRT1 reprograms endothelial cells to suppress angiogenesis after ischemia

Cited by 52 publications

References 44 publications

Exosomes derived from GDNF-modified human adipose mesenchymal stem cells ameliorate peritubular capillary loss in tubulointerstitial fibrosis by activating the SIRT1/eNOS signaling pathway

Exosomes derived from GDNF-modified human adipose mesenchymal stem cells ameliorate peritubular capillary loss in tubulointerstitial fibrosis by activating the SIRT1/eNOS signaling pathway

EV-origin: Enumerating the tissue-cellular origin of circulating extracellular vesicles using exLR profile

Circular RNA: metabolism, functions and interactions with proteins

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