ANGIOTENSIN II-INDUCED TRANSGLUTAMINASE 2 REGULATES P-38 MAP-KINASE LONG TERM EXPRESSION IN SHR VASCULAR SMOOTH MUSCLE CELLS: 2C.02

Abstract

Objective: Transglutaminase 2 (TG2) is ubiquitously expressed and induces transamidation and cross-linking of proteins. This process is important for cell-matrix interactions and vascular remodeling, and is modulated by angiotensin II (Ang II). We hypothesized that Ang II through the angiotensin type 1 receptor (AT1R) modulates TG2 expression, which differentially regulates MAP kinase expression in rat vascular smooth muscle cells (VSMCs). Methods: Mesenteric artery-derived VSMCs from Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR) were studied. Cells were stimulated with Ang II (100 nM) ± the AT1R blocker valsartan (Val 10 μM) or ± the TG2 inhibitor cystamine (CYS 10 μM). Expression of TG2, p38 MAPK, AT1R and AT2R was evaluated by immunoblotting. Results: Basal TG2 expression in SHR VSMCs was significantly higher compared to basal TG2 expression in WKY VSMCs (+28 ± 12%, p < 0.05). Ang II significantly increased TG2 expression only in SHR VSMCs compared to vehicle (+57 ± 19%, p < 0.05). Val significantly reduced Ang II-induced TG2 expression in SHR VSMCs. Basal AT1R expression in cells from WKY was lower compared to SHR (1.15 ± 0.2 AU vs 1.8 ± 0.1 AU, p < 0.05). Basal AT2R expression was 2-fold higher in SHR cells than in WKY (p < 0.05). Ang II had no effect on AT1R expression in either WKY or SHR. In presence of Ang II, AT2R expression was significantly increased in WKY and reduced in SHR (224.6 ± 65.13% vs 47.87 ± 11.95%, p < 0.05). After one-hour stimulation, Ang II increased p38 MAPK expression only in SHR (3-fold increase vs vehicle, p < 0.05). Ang II-induced p38 MAPK expression was significantly reduced by CYS. Conclusions: Ang II positively regulates TG2 expression in rat VSMCs via AT1R. TG2 plays a role in Ang II-induced p38 MAPK long-term production. These effects are particularly evident in SHR VSMCs which presented high basal levels of Ang II receptors and TG2.