Open AccessAutophagy dysfunction and regulatory cystatin C in macrophage death of atherosclerosis
Author(s) -
Li Wei,
Sultargis,
Siraj Nabeel,
Ward Liam J,
Pawlik Monika,
Levy Efrat,
Jovinge Stefan,
Bengtsson Eva,
Yuan XiMing
Publication year - 2016
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.12859
Subject(s) - autophagy , atg5 , oxysterol , apoptosis , cystatin c , clusterin , inflammation , macrophage , foam cell , programmed cell death , atheroma , apolipoprotein e , cancer research , endocrinology , medicine , biology , cholesterol , lipoprotein , biochemistry , disease , renal function , in vitro
Autophagy dysfunction in mouse atherosclerosis models has been associated with increased lipid accumulation, apoptosis and inflammation. Expression of cystatin C (CysC) is decreased in human atheroma, and CysC deficiency enhances atherosclerosis in mice. Here, we first investigated the association of autophagy and CysC expression levels with atheroma plaque severity in human atherosclerotic lesions. We found that autophagy proteins Atg5 and LC 3β in advanced human carotid atherosclerotic lesions are decreased, while markers of dysfunctional autophagy p62/ SQSTM 1 and ubiquitin are increased together with elevated levels of lipid accumulation and apoptosis. The expressions of LC 3β and Atg5 were positively associated with CysC expression. Second, we investigated whether CysC expression is involved in autophagy in atherosclerotic apoE‐deficient mice, demonstrating that CysC deficiency (CysC −/− ) in these mice results in reduction of Atg5 and LC 3β levels and induction of apoptosis. Third, macrophages isolated from CysC −/− mice displayed increased levels of p62/ SQSTM 1 and higher sensitivity to 7‐oxysterol‐mediated lysosomal membrane destabilization and apoptosis. Finally, CysC treatment minimized oxysterol‐mediated cellular lipid accumulation. We conclude that autophagy dysfunction is a characteristic of advanced human atherosclerotic lesions and is associated with reduced levels of CysC. The deficiency of CysC causes autophagy dysfunction and apoptosis in macrophages and apoE‐deficient mice. The results indicate that CysC plays an important regulatory role in combating cell death via the autophagic pathway in atherosclerosis.