Curcumin accelerates reendothelialization and ameliorates intimal hyperplasia in balloon-injured rat carotid artery via the upregulation of endothelial cell autophagy

Abstract

Delayed reendothelialization and intimal hyperplasia (IH) contribute to the failure of vascular interventions. Curcumin (Cur) has been used for various types of diseases with antioxidant, antiproliferative and anti-inflammatory effects. However, investigations involving the application of Cur in inhibiting IH are limited. The aim of the present study was to evaluate the potential therapeutic effects of Cur and its underlying mechanisms on a rat model of carotid artery (CA) intimal injury. In vitro, an endothelial cell (EC) migration assay was conducted using cultured primary human umbilical vein endothelial cells (HUVECs) that were exposed to Cur. In vivo, CA angioplasty injury was used to generate a rat model of intimal injury. CAs were collected at 3 days, and 1 and 4 weeks after injury, respectively, for western blot analysis and double-immunofluorescence analyses, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling staining, oxidative stress indicator analysis and hematoxylin and eosin staining of the neointima. In vivo, Cur significantly enhanced the migration and healing of HUVECs and simultaneously promoted microtubule-associated protein light chain 3-II (LC3-II) expression when HUVECs were subjected to an artificial scratch. In vitro, endangium from the Cur-treated rats exhibited a significantly reduced number of apoptotic ECs and oxidative stress level compared to that of the sham group. In addition, Cur treatment markedly improved quantification of the LC3-II concomitant with the downregulation of p62 in the injured CA. At 1 week following injury, sizable neointimal lesions had developed, although prominent intima thickening was not observed. At 4 weeks, apparent hemadostenosis occurred resulting from the exorbitance IH. Cur treatment markedly reduced the thickness of the neointimal lesion. It is noteworthy that high-dose Cur may have exerted more significant effects than low-dose Cur. Cur can potentially become a therapeutic drug for angiostenosis by imparting a protective effect that accelerates reendothelialization and ameliorates IH and was mediated by its pro-autophagic effect.

RETRACTED: Curcumin Improves Palmitate-Induced Insulin Resistance in Human Umbilical Vein Endothelial Cells by Maintaining Proteostasis in Endoplasmic Reticulum

“…The UPS impairment or inhibition will result in accumulation of misfolded and aggregated protein leading to compensative activation of autophagy ( Korolchuk et al, 2009 ; Jänen et al, 2010 ; Wang and Wang, 2015 ), aimed to clear up the aggregated or misfolded proteins that were previously thought to be targeted exclusively by the UPS ( Ding et al, 2007 ; Graziotto et al, 2012 ). Curcumin possesses the properties of proteasome inhibitor and autophagy inducer ( Milacic et al, 2008 ; Han et al, 2012 ; Chen et al, 2015 ). In the present study, we found that curcumin administration significantly suppressed peptidase activities of 20S proteasome, and compensatively activated autophagy under palmitate treatment ( Figure 5 ).…”

“…Previous studies have shown a significant association between ER stress and insulin resistance in endothelial cells ( Lenna et al, 2014 ; Gustavo Vazquez-Jimenez et al, 2016 ).When this ER stress is blocked pharmacologically, a complete recovery of insulin sensitivity is achieved ( Ozcan et al, 2004 ). Interestingly, curcumin acts as an inhibitor of both proteasome and ER stress ( Milacic et al, 2008 ; Han et al, 2012 ; Afrin et al, 2015 ; Chen et al, 2015 ; Rashid and Sil, 2015 ; Wang et al, 2016 ). Given that the proteasome pathway and autophagy has been demonstrated to interact each other ( Korolchuk et al, 2009 ; Jänen et al, 2010 ; Wang and Wang, 2015 ), we rationally and logically speculated that curcumin might maintain ER proteostasis through activating autophagy, leading to suppression of ER stress with subsequent improvement of insulin sensitivity.…”

<p>Inhibitory Effect of Curcumin on Artery Restenosis Following Carotid Endarterectomy and Its Associated Mechanism in vitro and in vivo</p>

“…23 Chen et al demonstrated that Cur could accelerate reendothelialization and ameliorate intimal hyperplasia of rat carotid artery tissues by promoting endothelial cell autophagy. 24 In addition, a previous study has shown that inflammatory cells can participate in intimal restenosis by secreting inflammatory factors to stimulate the increase of VSMCs and their migration to the subintima. 25 The proliferation of VSMCs and the carotid artery restenosis following vascular injury are associated with the increase in the levels of reactive oxygen species (ROS).…”

TNF‐α promotes survival and migration of MSCs under oxidative stress via NF‐κB pathway to attenuate intimal hyperplasia in vein grafts

“…Disappointingly, several lines of evidence suggest that approximately 40–50% of these vein grafts ultimately result in stenosis and even occlusion . The primary cause of stenosis of vein grafts is oxidative stress caused by injury of the endothelium .…”

“…Injection of MSCs has been utilized to alleviate atherosclerosis, myocardial ischaemia and vascular balloon injury . Experiments have shown that oxidative stress exists in vascular intima and the blood circulation following both vein grafting and vascular injury, after a short period of time and lasting for several weeks . Furthermore, recent studies have demonstrated that excessive and/or persistent stimulation of oxidative stress can reduce the functions of MSCs and increase apoptosis .…”