Angiotensin II activates nuclear transcription factor-kappaB in aorta of normal rats and in vascular smooth muscle cells of AT1 knockout mice.
BACKGROUND
Nuclear factor-kappaB (NF-kappaB) regulates many genes involved in vascular physiopathology. Angiotensin II (Ang II) participates in the pathogenesis of several cardiovascular diseases. In a model of atherosclerosis, we have noted NF-kappaB activation in the neointimia lesion that was decreased by angiotensin-converting enzyme (ACE) inhibitors. However, the potential direct effect of Ang II in the vascular activation of NF-kappaB has not been completely elucidated.


METHODS
We first investigated whether Ang II elicited in vivo activation of NF-kappaB in large vessels of normal rats by systemic infusion of Ang II (50 ng/kg/min, s.c.) into rats for 72 h. In order to investigate the receptor involved in this process, we also studied the direct effect of Ang II on cultured vascular smooth muscle cells (VSMCs) from wild-type and AT1 knockout mice.


RESULTS
Ang II-infused rats showed activated NF-kappaB in the endothelial and vascular smooth muscle cells of the aorta (southwestern histochemistry). In cultured VSMCs from wild-type mice, Ang II increased NF-kappaB activity that was partially inhibited by AT1 (losartan) and AT2 (PD123319) antagonists. In VSMC from AT1 knockout mice, Ang II also activated NF-kappaB.


CONCLUSIONS
These data show that Ang II via AT1 and AT2 activates NF-kappaB in vascular cells both in vivo and in vitro, and suggest a potential involvement of the AT2 receptor in the pathogenesis of vascular diseases, including hypertension and atherosclerosis.
Ruiz-Ortega
M
M
Laboratory of Vascular and Renal Pathology, Fundación Jiménez Díaz, Universidad Autónoma, Madrid, Spain.
Lorenzo
O
O
Rupérez
M
M
Suzuki
Y
Y
Egido
J
J
D000804:Angiotensin II / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism*; D001483:Base Sequence; D001665:Binding Sites; D002478:Cells, Cultured; D016384:Consensus Sequence; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D007093:Imidazoles / Q000494:pharmacology; D019808:Losartan / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism
D057911:Angiotensin Receptor Antagonists; D007093:Imidazoles; D016328:NF-kappa B; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D014157:Transcription Factors; D000804:Angiotensin II; C073402:PD 123319; D019808:Losartan