Contribution of transcription factor EB to adipoRon-induced inhibition of arterial smooth muscle cell proliferation and migration

Abstract

Abnormal vascular smooth muscle cell (SMC) dedifferentiation with increased proliferation and migration during pathological vascular remodeling is associated with vascular disorders, such as atherosclerosis and in-stent restenosis. AdipoRon, a selective agonist of adiponectin receptor, has been shown to protect against vascular remodeling by preventing SMC dedifferentiation. However, the molecular mechanisms that mediate adipoRon-induced SMC differentiation are not well understood. The present study aimed to elucidate the role of transcription factor EB (TFEB), a master regulator of autophagy, in mediating adipoRon’s effect on SMCs. In cultured arterial SMCs, adipoRon dose-dependently increased TFEB activation, which is accompanied by upregulated transcription of genes involved in autophagy pathway and enhanced autophagic flux. In parallel, adipoRon suppressed serum-induced cell proliferation and caused cell cycle arrest. Moreover, adipoRon inhibited SMC migration as characterized by wound-healing retardation, F-actin reorganization, and matrix metalloproteinase-9 downregulation. These inhibitory effects of adipoRon on proliferation and migration were attenuated by TFEB gene silencing. Mechanistically, activation of TFEB by adipoRon is dependent on intracellular calcium, but it is not associated with changes in AMPK, ERK1/2, Akt, or molecular target of rapamycin complex 1 activation. Using ex vivo aortic explants, we demonstrated that adipoRon inhibited sprouts that had outgrown from aortic rings, whereas lentiviral TFEB shRNA transduction significantly reversed this effect of adipoRon on aortic rings. Taken together, our results indicate that adipoRon activates TFEB signaling that helps maintain the quiescent and differentiated status of arterial SMCs, preventing abnormal SMC dedifferentiation. This study provides novel mechanistic insights into understanding the therapeutic effects of adipoRon on TFEB signaling and pathological vascular remodeling.

Aerobic Exercise Alleviates Abnormal Autophagy in Brain Cells of APP/PS1 Mice by Upregulating AdipoR1 Levels

“…Exercise upregulates the AdipoR1 levels in AD mice brain. AdipoR agonists have been reported to promote TFEB’s nuclear translocation and the expression of TFEB-controlled autophagic genes, such as cathepsin D, lysosomal-associated membrane protein 1 (LAMP1), and ATPase H+ transporting V1 subunit H (Atp6v1h), thereby enhancing lysosomal function and autophagic flux [ 33 , 34 , 35 ]. It is suggested that aerobic exercise may promote the nuclear translocation of TFEB in the brain cells of APP/PS1 mice by upregulating the AdipoR1 signaling pathway.…”

“…Studies have shown that decreased lysosomal acidification accompanied by impaired autophagic substrate clearance is an important factor in the induction of AD-related pathologies such as Aβ deposition [ 40 ]. TFEB regulates the expression of lysosomal-function-related genes such as LAMP1 and cathepsin D and autophagy-related genes, thereby enhancing the autophagy–lysosomal pathway, reducing neural apoptosis, and exerting neuroprotective effects [ 35 , 49 ]. Drug treatment enhances the autophagolysosomal pathway by activating TFEB, thereby promoting the degradation of toxic proteins in AD models, and PP2A plays an important role in promoting TFEB’s nuclear translocation [ 33 ].…”

Cytoglobin overexpression facilitates proliferation and migration of vascular smooth muscle cells

“…The present study provides evidence for the molecular basis of CYGB contribution to vascular remodeling. VSMC migration is critical in many physiological and pathological processes [23,24]. Herein, we show that overexpression of CYGB provided faster migration rates in the scratch monolayer cell wound assay compared to the control.…”

ATF4 promotes brain vascular smooth muscle cells proliferation, invasion and migration by targeting miR-552-SKI axis

“…Wang et al revealed the contribution of TF EB to adipoRon-induced inhibition of arterial smooth muscle cell proliferation and migration [ 28 ]. In our study, JASPAR software online was used to predict TFs regulating promoters of miR-552 and the ATF4 were determined by qRT-PCR assay.…”