Protein Inhibitor of Activated STAT3 Suppresses Oxidized LDL-induced Cell Responses during Atherosclerosis in Apolipoprotein E-deficient Mice

Abstract

Atherosclerosis is a serious public health concern. Excessive inflammatory responses of vascular cells are considered a pivotal pathogenesis mechanism underlying atherosclerosis development. It is known that Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) signalling plays an important role in atherosclerosis progression. Protein inhibitor of activated STAT3 (PIAS3) is the key negative regulator of JAK/STAT3 signalling. However, its effect on atherogenesis is unknown. Here, we observed that PIAS3 levels are reduced in atherosclerotic lesions and that PIAS3 expression decreases in conjunction with increases in interleukin-6 expression and atherosclerosis severity. Oxidized low-density lipoprotein (ox-LDL), an atherogenic stimulus, reduced PIAS3 expression, an effect that may be attributed to nitric oxide synthesis upregulation. In turn, PIAS3 overexpression effectively suppressed ox-LDL-induced inflammation, lipid accumulation and vascular smooth muscle cell proliferation. These results indicate that PIAS3 is a critical repressor of atherosclerosis progression. The findings of this study have contributed to our understanding on the pathogenesis of atherosclerosis and have provided us with a potential target through which we can inhibit atherosclerosis-related cellular responses.

SOCS1-targeted therapy ameliorates renal and vascular oxidative stress in diabetes via STAT1 and PI3K inhibition

“…Moreover, STAT1/STAT3 transcription factors physically interact with the gene promoter region of Nox1 and Nox4 for positive upregulation [52]. In vascular cells and macrophages, either JAK2 inhibitor or STAT1/ STAT3 knockdown blunted Nox activity and expression and subsequently hampered ROS production [52][53][54]. In the context of diabetes, our in vitro results indicate that hyperglycemia and a combination of pro-inflammatory cytokines act on renal, vascular, and phagocytic cells to generate ROS and maintain cell injury, and effect blocked by Nox inhibitors.…”

Long Non-Coding RNAs Link Oxidized Low-Density Lipoprotein With the Inflammatory Response of Macrophages in Atherogenesis

“…In contrast, MIAT was also found to inhibit ox-LDL-induced apoptosis in HCAMCs partly by inhibition of miR-181b, which induces the upregulation of signal transducer and activator of transcription 3 (STAT3) in vitro (87). Notably, STAT3 is a critical inflammatory mediator in atherosclerosis and inhibition of STAT3 suppressed the ox-LDL induced inflammation in high-fat fed ApoE −/− mice (124). MIAT promotes inflammation and increased lipid content to accelerate atherosclerosis development, however its effect on apoptosis of SMCs needs further study.…”

Anti-JNK2 peptide–siRNA nanostructures improve plaque endothelium and reduce thrombotic risk in atherosclerotic mice

“…immunofluorescence-stained sections indicated that 42.66% of all cells in plaques from control animals exhibited activated NFκB signaling, whereas only 22.48% of cells were positive in animals undergoing treatment ( Figure 3C); a 47% reduction. Given the cross talk between NFκB and STAT3 [43][44][45][46] and the crucial role of STAT3 signaling in the progression of atherosclerosis, [47][48][49] STAT3 protein expression in the whole aorta was evaluated ( Figure 3D and E). p5RHH-JNK2 siRNA nanoparticle-treated animals exhibited a 46% reduction in whole-aorta STAT3 expression (P=0.004) compared to controls.…”