Angiotensin AT1 receptor antagonists exert anti-inflammatory effects in spontaneously hypertensive rats.
OBJECTIVE
Although the main therapeutic effect of angiotensin AT1 receptor antagonists is to decrease blood pressure, they also exert anti-inflammatory effects in the cardiovascular system. However, the underlying mechanisms remain unclear. We investigated the inhibitory effect of AT1 antagonists on the chemokine monocyte chemoattractant protein 1 (MCP-1) and its receptor C-C chemokine receptor 2 (CCR2) in rat monocytes and aortas.


METHODS
Spontaneous hypertensive rats (SHRs) were treated with the AT1 antagonists losartan or telmisartan for 4 weeks, and Wistar-Kyoto rats (WKYs) were used as normotensive controls. Systolic arterial pressure was measured, and the number of macrophages in the aortic vessel wall was assessed by anti-ED-1 antibody immunolabelling.


RESULTS
Compared with WKYs, SHRs showed significantly increased ED-1 positive macrophages in the aortic wall, which were decreased after high doses of losartan or telmisartan. Low doses of losartan did not improve blood pressure significantly as did the high doses, but markedly decreased macrophage infiltration in the vessel wall. AT1 antagonists, particularly at high doses, improved aortic remodeling in SHR. At the molecular level, AT1 antagonists attenuated the expression of MCP-1 and CCR2 in the aorta and peripheral blood monocytes and lowered the serum level of MCP-1. In addition, Western blotting showed that AT1 antagonists inhibited the phosphorylation of Akt in mouse monocytes.


CONCLUSIONS
AT1 antagonism inhibited vessel wall inflammation and inhibition of PI3K/Akt may be involved in the modulation of the MCP-1/CCR2 system by AT1 antagonists in SHRs.
Dai
Q
Q
Department of Cardiology, Shanghai First People's Hospital, Jiaotong University, Shanghai, China.
Xu
M
M
Yao
M
M
Sun
B
B
D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000276:immunology; D001011:Aorta / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000494:pharmacology; D001565:Benzoates / Q000008:administration & dosage* / Q000494:pharmacology; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000097:blood / Q000235:genetics; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000276:immunology; D019808:Losartan / Q000008:administration & dosage* / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000276:immunology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D000077333:Telmisartan
D047228:Angiotensin II Type 1 Receptor Blockers; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000911:Antibodies, Monoclonal; D001562:Benzimidazoles; D001565:Benzoates; C111835:CCL2 protein, human; C491766:Ccl2 protein, rat; C515336:Ccr2 protein, rat; D018932:Chemokine CCL2; D054390:Receptors, CCR2; D051057:Proto-Oncogene Proteins c-akt; D019808:Losartan; D000077333:Telmisartan