A Novel Anticancer Therapeutic Strategy to Target Autophagy Accelerates Radiation-Associated Atherosclerosis.

Abstract

Autophagy inhibition is a novel therapeutic strategy suggested for patients with advanced cancer, especially those who have undergone radiation therapy. In the present study, we investigated whether autophagy inhibitors accelerate the progression of radiation-associated atherosclerosis (RAA). Eight-week-old apolipoprotein (ApoE^-/-) mice were fed a Western diet, and their left common carotid arteries were partially ligated to induce atherogenesis. Four weeks later, local ionizing radiation (IR) at a dose of 5 or 10 Gy was used to induce RAA in the left common carotid artery. After another 4 weeks, severe plaque burden associated with increased macrophage infiltration and lipid deposition, reduced smooth muscle cells, and decreased collagen expression was observed. In addition, these changes occurred in a dose-dependent manner. Improved autophagic flux caused by IR was observed in both macrophages of the atherosclerotic plaque and peritoneal macrophages in vitro. The inhibition of autophagic flux by chloroquine (50 mg/kg/d) further accelerated the progression of RAA in the left common carotid arteries of ApoE^-/- mice. Furthermore, chloroquine treatment exacerbated IR-induced p65 nuclear translocation, IκBα degradation, and transcription of nuclear factor-κB (NF-κB) target genes in peritoneal macrophages. IR promotes atherogenesis and increases autophagic flux. In addition, autophagy inhibition by chloroquine accelerates the progression of RAA lesions by stimulating NF-κB-mediated inflammatory responses in macrophages.