GSTpi protects against angiotensin II-induced proliferation and migration of vascular smooth muscle cells by preventing signal transducer and activator of transcription 3 activation

Abstract

Angiotensin II (Ang II)-elicited excessive proliferation, hypertrophy and migration of vascular smooth muscle cells (VSMCs) are vital to the pathogenesis of atheroclerosis. Glutathione S-transferase pi (GSTpi) exists extensively in various kinds of cells and protects cells against different stresses. However, knowledge remains limited about what GSTpi acts in VSMCs. We investigated the effect of GSTpi on Ang II-induced VSMC proliferation, hypertrophy and migration and its latent mechanism. Overexpression and RNAi experiments demonstrated that GSTpi inhibited Ang II-induced proliferation, hypertrophy and migration of VSMCs and arrested progression of cell cycle from G0/G1 to S phase. Immunoprecipitation, mass spectrometry and confocal microscopy analyses showed that GSTpi directly associated with signal transducer and activator of transcription 3 (STAT3) to prevent Ang II-triggered binding of Src to STAT3 and thus suppressed Ang II-stimulated phosphorylation and nuclear translocation of STAT3, as well as cyclin D1 expression. In contrast, GSTpi didn't affect Ang II-activated extracellular signal-regulated kinase (ERK1/2). GSTpi acts as a negative regulator to prevent Ang II-triggered proliferative signaling in VSMCs, suggesting that it may protect vessels against the stresses associated with atherosclerosis formation.

Regulation of Endothelial Permeability by Glutathione S-Transferase Pi Against Actin Polymerization

“…We also found that GSTpi could bind tumor necrosis factor receptor-associated factor 2 (TRAF2) in the TRAF domain to block the TRAF2-apoptosis signal-regulating kinase 1 (ASK1)-JNK signaling cascade induced by TNF-α, and as a result, inhibited cell apoptosis [15]. Furthermore, GSTpi prevented the proliferation and migration of vascular smooth muscle cell [16]. These results all suggest that GSTpi might regulate endothelial barrier function in ECs.…”

“…WhenTyr7 is substituted with Phe, the transferase activity of GSTpi decreases by 55 times [16]. Since most of the function of GSTpi is related to its enzyme activity, we investigated whether inhibition of the increase of TNF-α-induced EC permeability was related to GSTpi transferase activity.…”

“…Additionally GSTpi is high expressed in ECs, suggesting that it may be involved in the regulation of endothelial permeability [15, 16]. To investigate the effect of GSTpi on TNF-α-induced endothelial cell permeability increases, we applied TNF-α (50ng/mL) for 2, 4, or 6hand measured FITC-Dextran 40 fluorescence values under GSTpi overexpression or siRNA interference in HUVECs condition.…”

“…Our previous studies have demonstrated anti-inflammatory functions of GSTpi at the cellular and animal levels. We have also found that GSTpi binds to STAT3to protect vascular smooth muscle cells (VSMCs) against angiotensin II-induced proliferation of VSMCs and vascular remodeling [15, 16]. GSTpi exists extensively in various cell types including ECs, but it is unclear whether GSTpi protects ECs from stimulation by pro-inflammatory cytokines.…”

Changes in levels of angiotensin II and its receptors in a model of inverted stress-induced cardiomyopathy

“…Angiotensin II is also implicated in the pathophysiological processes related to myocardial remodeling [10, 11]. Angiotensin II activates several nuclear transcription factors (such as signal transducer and activator of transcription (STAT) and cyclic adenosine monophosphate (cAMP) response element-binding (CREB) protein) by promoting fibroblast proliferation that leads to myocardial remodeling [12,13]. …”