Angiotensin II Signaling in Vascular Smooth Muscle Cells Under High Glucose Conditions

Abstract

The mechanisms responsible for the accelerated cardiovascular disease in diabetes, as well as the increased hypertrophic effects of angiotensin II (Ang II) under hyperglycemic conditions, are not very clear. We examined whether the culture of vascular smooth muscle cells (VSMC) under hyperglycemic conditions to simulate the diabetic state can lead to increased activation of key growth- and stress-related kinases, such as the mitogen-activated protein kinases (MAPKs), in the basal state and in response to Ang II. Treatment of porcine VSMC for short time periods (0.5 to 3 hours) with high glucose (HG; 25 mmol/L) markedly increased the activation of the extracellular signal-regulated kinase (ERK1/2) and c-Jun/N-terminal kinase (JNK) relative to cells cultured in normal glucose (NG; 5.5 mmol/L). p38 MAPK also was activated by HG, and this effect remained sustained for several hours. Ang II treatment increased the activity of all 3 families of MAPKs. Ang II-induced ERK activation was potentiated nearly 2-fold in cells treated with HG for 0.5 hour. However, Ang II-induced JNK was not altered. In VSMC cultured for 24 hours with HG, Ang II and HG displayed an additive response on p38 MAPK activity. MAPKs can lead to activation of transcription factors such as activator protein-1 (AP-1). HG alone significantly increased AP-1 DNA-binding activity. Furthermore, Ang II and HG combined had additive effects on AP-1 activity. These results suggest that increased activation of specific MAPKs and downstream transcription factors, such as AP-1, may be key mechanisms for the increased VSMC growth potential of HG alone and of Ang II under HG conditions.

Breviscapine inhibits high glucose-induced proliferation and migration of cultured vascular smooth muscle cells of rats via suppressing the ERK1/2 MAPK signaling pathway

“…As previously reported [7,10,11,25] , both the PKC inhibitor Ro 31-8220 and the MEK1/2 inhibitor PD 98059 abrogated the high glucoseenhanced proliferation and migration of VSMCs. Thus, the PKC and MAPK pathways were both responsible for mediating the proliferative-and migratory-promoting response of VSMCs in high glucose medium.…”

“…Previous studies have demonstrated that VSMCs that are cultured under hyperglycemic conditions displayed enhanced proliferative and migratory responses compared to cells that are www.chinaphar.com He M et al Acta Pharmacologica Sinica npg cultured under euglycemic conditions, and it has been suggested that protein kinase C (PKC) signal transduction may play an important role in this effect [7,9,10] . Other studies have shown that activation of the mitogen-activated protein kinase (MAPK) pathway may contribute to the increased proliferation and migration of VSMCs in response to hyper glycemia [10,11] .…”

Angiotensin II induces human TGF-β1 promoter activation: similarity to hyperglycaemia

“…In a recent study with vascular smooth muscle cells, an additive response has been described after stimulation with high glucose and ang II on p38 MAPK activity and AP-1 DNA binding [26]. However, the experimental design was different.…”

“…smooth muscle cells and renal tubular epithelial cells, indicate an activation of protein kinase C and p38 MAPK by ang II [11,26,27,28]. Furthermore, other reports have shown that ang II induces the DNA-binding activity of AP-1 proteins [29,30,31,32].…”

Novel E2F decoy oligodeoxynucleotides inhibit in vitro vascular smooth muscle cell proliferation and in vivo neointimal hyperplasia

“…[32][33][34] We examined the effect of high glucose on E2F DNA-binding activity in VSMCs and cell cycle regulatory genes, and proliferation of VSMCs. Our data show that E2F DNA-binding activity and luciferase activity of the [E2F] Â 4-luciferase construct were significantly increased after treatment with high concentrations of glucose in VSMCs.…”