Caffeine prevents restenosis and inhibits vascular smooth muscle cell proliferation through the induction of autophagy

Abstract

Caffeine is among the most highly consumed substances worldwide, and it has been associated with decreased cardiovascular risk. Caffeine inhibits the proliferation of vascular smooth muscle cells (VSMCs); however, little is known about the mechanism(s). Here, we demonstrated that caffeine decreased VSMC proliferation and induced autophagy in an in vivo vascular injury model of restenosis. Further, we studied the effects of caffeine in primary human and mouse aortic VSMCs and immortalized mouse aortic VSMCs. Caffeine decreased cell proliferation, and induced autophagy flux via inhibition of mTOR signaling in these cells. Genetic deletion of the key autophagic gene, ATG5, and its adaptor protein, SQSTM1/p62, showed the anti-proliferative effect by caffeine was dependent upon autophagy. Interestingly, caffeine also decreased Wntsignaling and the expression of two Wnt target genes, AXIN2 and Cyclin D1. This effect was mediated by autophagic degradation of a key member of the Wnt signaling cascade, DVL2, by caffeine to decrease Wnt signaling and cell proliferation. SQSTM1/p62, MAP1LC3B-II and Dvl2were also shown to interact with each other, and the overexpression of Dvl2 counteracted the inhibition of cell proliferation by caffeine. Taken together, our in vivo and in vitro findings have demonstrated that induction of autophagy by caffeine significantly reduced vascular restenosis.Caffeine reduced VSMC proliferation by inhibiting Wnt signaling via stimulation of autophagy.Our findings suggest that caffeine and other autophagy-inducing drugs may represent novel cardiovascular therapeutic tools to protect against restenosis after angioplasty and/or stent placement.

The roles of METTL3 on autophagy and proliferation of vascular smooth muscle cells are mediated by mTOR rather than by CDK1

“…Except for autophagy regulation, mTOR also contributes to proliferation regulation in an autophagy-dependent and -independent manner [ 13 , 35 ]. For example, caffeine suppressed VSMC proliferation and induced autophagy by inhibiting mTOR signaling and WNT signaling in an in vivo vascular injury-induced restenosis model [ 1 ]. However, AdipoRon (a small-molecule adiponectin receptor agonist) can alleviate neointimal hyperplasia after angioplasty by targeting mTOR signaling independent of AMPK activation [ 13 ].…”

“…For example, over-proliferation of VSMCs will lead to neointima formation, while insufficient proliferation will result in vascular structure disorder or even rupture. Autophagy was reported to be involved in VSMC proliferation and survival [ 1 , 2 ]. However, the effect of autophagy on VSMC proliferation is controversial.…”

Ginkgolide B Blocks Vascular Remodeling after Vascular Injury via Regulating Tgfβ1/Smad Signaling Pathway

“…No Influence of Tgfβ1/Smad Signal Pathway in Human Umbilical Vein Endothelial Cells (HUVECs). Vascular remodeling and further restenosis are primarily caused by the proliferation and migration of endothelial cells or VSMCs [35][36][37][38][39][40]. To further confirm the underlying mechanism of GB in vitro, a Tgfβ1-stimulated HUVEC model was first established.…”

Diagnostic Ultrasound-Based Investigation of Central vs. Peripheral Arterial Changes Consequent to Low-Dose Caffeine Ingestion

“…The binding of adenosine to adenosine 2A (A 2A ) receptors induces blood vessel dilation and regulates blood flow [ 5 , 6 ]. However, when caffeine enters the blood vessels, it binds to the A 2A receptors in vascular smooth muscle cells and blocks adenosine binding, preventing blood vessel dilation and causing continued contraction [ 7 , 8 ]. These changes affect central blood vessels, such as the common carotid artery (CCA), which supplies blood to the brain, rather than peripheral blood vessels, such as the radial artery (RA).…”