Protein deglycase DJ‐1 deficiency induces phenotypic switching in vascular smooth muscle cells and exacerbates atherosclerotic plaque instability

Abstract

Protein deglycase DJ‐1 (DJ‐1) is a multifunctional protein involved in various biological processes. However, it is unclear whether DJ‐1 influences atherosclerosis development and plaque stability. Accordingly, we evaluated the influence of DJ‐1 deletion on the progression of atherosclerosis and elucidate the underlying mechanisms. We examine the expression of DJ‐1 in atherosclerotic plaques of human and mouse models which showed that DJ‐1 expression was significantly decreased in human plaques compared with that in healthy vessels. Consistent with this, the DJ‐1 levels were persistently reduced in atherosclerotic lesions of ApoE−/− mice with the increasing time fed by western diet. Furthermore, exposure of vascular smooth muscle cells (VSMCs) to oxidized low‐density lipoprotein down‐regulated DJ‐1 in vitro. The canonical markers of plaque stability and VSMC phenotypes were evaluated in vivo and in vitro. DJ‐1 deficiency in Apoe−/− mice promoted the progression of atherosclerosis and exaggerated plaque instability. Moreover, isolated VSMCs from Apoe−/−DJ‐1−/− mice showed lower expression of contractile markers (α‐smooth muscle actin and calponin) and higher expression of synthetic indicators (osteopontin, vimentin and tropoelastin) and Kruppel‐like factor 4 (KLF4) by comparison with Apoe−/−DJ‐1+/+ mice. Furthermore, genetic inhibition of KLF4 counteracted the adverse effects of DJ‐1 deletion. Therefore, our results showed that DJ‐1 deletion caused phenotype switching of VSMCs and exacerbated atherosclerotic plaque instability in a KLF4‐dependent manner.

Vascular Smooth Muscle Cells Phenotypic Switching in Cardiovascular Diseases

“…Although atherosclerosis was initially thought to be a problem that plagued people concentrated in developed countries, it has become apparent that it is a global matter. With the increasingly effective prevention and control measures for infectious diseases, the improvement of health services, and better access to medical care, people now have a longer life expectancy, and they are more likely to be exposed to the adverse consequences of atherosclerosis [ 24 , 25 ], such as myocardial infarction due to thrombus formation when a plaque ruptures or erosion blocks the blood flow [ 26 ]. Although middle- to older-aged people are the primary population affected, an increasing number of younger women are now at risk, and an increasing proportion of patients of advanced age are women [ 27 , 28 ].…”

“…A new long-stranded non-coding RNA (lncRNA), PEBP1P2, can curb the growth and migration of VSMCs by directly binding to CDK9 [ 5 ]. DJ-1 deficiency leads to VSMCs phenotype switching and is dependent on KLF4 to exacerbate atherosclerotic plaque instability [ 24 ].…”

Ginsenoside Rh1 Inhibits Angiotensin II-Induced Vascular Smooth Muscle Cell Migration and Proliferation through Suppression of the ROS-Mediated ERK1/2/p90RSK/KLF4 Signaling Pathway

“…KLF4 has been reported to regulate the phenotypic switching of VSMCs under the stimulation of several factors, including PDGF and oxidized phospholipids, as well as in atherosclerotic lesions [13,32,49,50]. Indeed, the depletion of KLF4 was found to inhibit the downregulation of contractile markers, such as α-SMA and calponin, and the upregulation of synthetic markers, including vimentin and OPN [32,50].…”

“…KLF4 is a key regulator of SMC phenotypic switching [32]. Because we found that Rh1 had an effect on Ang II-induced changes in the protein levels of contractile and synthetic markers, the protein expression of KLF4 was examined.…”

Clinical implications of inflammation in atheroma formation and novel therapies in cardiovascular diseases

“…Notably, the key role of miRNAs in such a dedifferentiation process by regulating intimal thickening has been reported, with the miR-146b-3p/PIK3CG axis as a representative example ( Zhuang et al, 2021 ). Of note, the central role of transcription factor KLF4 in this phenotypic change triggered by several stimuli including the exposure of contractile vascular SMC to oxidized LDL has been highlighted ( Wang et al, 2021 ). Parallelly, the phenotypic switching undergone by cancerous cells, from a well-differentiated phenotype towards a cancer stem-like one, which could also be termed as a “dedifferentiation process” has been widely described, with crucial roles during tumour progression of enhancing cellular aggressiveness and metastasis ( Sandiford et al, 2021 ).…”