Angiotensin II is associated with activation of NF-κB-mediated genes and downregulation of PPARs

Abstract

Angiotensin II (ANG II) promotes vascular inflammation through nuclear factor-kappaB (NF-kappaB)-mediated induction of pro-inflammatory genes. The role of peroxisome proliferator-activated receptors (PPARs) in modulating vascular inflammation and atherosclerosis in vivo is unclear. The aim of the present study was to examine the effects of ANG II on PPARs and NF-kappaB-dependent pro-inflammatory genes in the vascular wall in an in vivo model of atherosclerosis and aneurysm formation. Six-month-old male apolipoprotein E-deficient (apoE-KO) mice were treated with ANG II (1.44 mg/kg per day for 30 days). ANG II enhanced vascular inflammation, accelerated atherosclerosis, and induced formation of abdominal aortic aneurysms. These effects of ANG II in the aorta were associated with downregulation of both PPAR-alpha and PPAR-gamma mRNA and protein and an increase in transcription of monocyte chemotactic protein-1 (MCP-1), macrophage-colony stimulating factor (M-CSF), endothelial-selectin (E-selectin), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) throughout the entire aorta. ANG II also activated NF-kappaB with increases in both p52 and p65 NF-kappaB subunits. In summary, these in vivo results indicate that ANG II, through activation of NF-kappaB-mediated pro-inflammatory genes, promotes vascular inflammation, leading to acceleration of atherosclerosis and induction of aneurysm in apoE-KO mice. Downregulation of PPAR-alpha and -gamma by ANG II may diminish the anti-inflammatory potential of PPARs, thus contributing to enhanced vascular inflammation.

Gemfibrozil decreases atherosclerosis in experimental diabetes in association with a reduction in oxidative stress and inflammation

“…Angiotensin II (AGII) has been shown to exert effects on both inflammation and oxidative stress via the AGII receptor subtype 1 [31,32]. In the current study we demonstrated a reduction in Agtr1 gene expression in the aortae of both control (p<0.05) and diabetic mice (p<0.05) with gemfibrozil treatment ( Table 2).…”

Obesidade e doença arterial coronariana: papel da inflamação vascular

“…The increased production of angiotensinogen by the adipose tissue is associated with high blood pressure and angiogenesis, both related to endothelial dysfunction. Similarly, the angiotensin II acts in the formation of oxygen-derived free radicals, decreasing the availability of nitric oxide and causing damages to the vascular tissue 31 .…”

Molecular Dissection of Angiotensin II–Activated Human LOX-1 Promoter

“…16,17 Further, pretreatment of endothelial cells with anti-oxidants attenuates Ang II-and oxLDL-induced LOX-1 expression, 16,17 implying a common oxidant signaling pathway. As such, it appears that Ang II may activate LOX-1 promoter through the same mechanism as oxLDL.…”

“…The activation of NF-B p50 subunit in response to Ang II in endothelial cells is controversial. Some investigators 20,21 have shown the activation of both p50 and p65 subunits by Ang II, whereas others 16,22 showed the activation of only NF-B p65 by Ang II. We performed EMSA-supershift assay with antibody against NF-B p50 subunit, and found that Ang IIinduced shifted band was somewhat attenuated by the NF-B p50 antibody (data not shown).…”