Impact of RGS2 deficiency on the therapeutic effect of telmisartan in angiotensin II-induced aortic aneurysm.
Regulator of G-protein signaling 2 (RGS2) negatively regulates the signaling of G-protein-coupled receptors, such as the angiotensin II (AngII) type 1 receptor by accelerating the inactivation of Gαq. Rgs2-deficient mice show increased sensitivity and prolonged responsiveness to vasoconstrictors, and genetic variations in the RGS2 gene are associated with hypertension in humans. This study aimed to clarify whether Rgs2 deficiency contributes to the development of vascular remodeling and therapeutic efficacy of the angiotensin receptor blocker telmisartan on atherosclerotic vascular damage. We treated Rgs2(+/+), Rgs2(+/-) and Rgs2(-/-) mice with saline (control group), AngII (1000 ng per kg per min, AngII group) or low-dose telmisartan (0.3 mg per kg per day) with AngII infusion (AngII+Telmi group) for 4 weeks. For all genotypes, the AngII groups exhibited significantly higher blood pressure, a higher mortality rate and a higher incidence of aortic aneurysm than the respective control group. Interestingly, aneurysm incidence was decreased in the AngII+Telmi group compared with the AngII group in Rgs2(-/-) mice (6.7 vs. 42.9%, P<0.05), but not in Rgs2(+/+) mice (38.9 vs. 40.0%). Moreover, in Rgs2(-/-) mice, the AngII+Telmi group exhibited significant improvement in survival, reduction of enlarged aortic diameter, inhibition of superoxide production and suppression of NAD(P)H oxidase activity compared with the AngII group. Thus, Rgs2 deficiency potentiates the vascular protection effect of low-dose telmisartan. Our results suggest that angiotensin receptor blocker may be useful for protection from cardiovascular events in hypertensive subjects with risk alleles in the RGS2 gene.
Matsumoto
Sachiko
S
Research Institute, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
Kamide
Kei
K
Banno
Fumiaki
F
Inoue
Nobutaka
N
Mochizuki
Naoki
N
Kawano
Yuhei
Y
Miyata
Toshiyuki
T
D000483:Alleles; D000704:Analysis of Variance; D000804:Angiotensin II / Q000008:administration & dosage*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001014:Aortic Aneurysm / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics; D001562:Benzimidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D001565:Benzoates / Q000494:pharmacology / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics; D005838:Genotype; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D020710:RGS Proteins / Q000235:genetics*; D013481:Superoxides / Q000378:metabolism; D000077333:Telmisartan
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D020710:RGS Proteins; C105345:Rgs2 protein, mouse; D013481:Superoxides; D000804:Angiotensin II; D000077333:Telmisartan