Impact of RGS2 deficiency on the therapeutic effect of telmisartan in angiotensin II-induced aortic aneurysm

Abstract

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 Gaq. 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 +/À and Rgs2 À/À 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 À/À mice (6.7 vs. 42.9%, Po0.05), but not in Rgs2 +/+ mice (38.9 vs. 40.0%). Moreover, in Rgs2 À/À 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.

Regulators of G-Protein-Signaling Proteins: Negative Modulators of G-Protein-Coupled Receptor Signaling

“…Both RGS2 þ/À and RGS2 À/À mice are very hypertensive with increased systemic and renal vascular resistance and hypertrophy of the renal arterial vasculature (Fujio, 2010;Gurley et al, 2010;Heximer et al, 2003;Matsumoto et al, 2010;Momen et al, 2014;Ota et al, 2013;Sjogren et al, 2012;Sugimoto et al, 2010;Tsang et al, 2010). These RGS2 absent mice have excessive and prolonged Ca þþ signaling to vasconstrictors such as ATP acting on P2Y receptors.…”

The RGS2 (-391, C>G) Genetic Variation Correlates to Antihypertensive Drug Responses in Chinese Patients with Essential Hypertension

“…One study found that RGS2 mRNA levels increased because of the RGS2 (-391 C>G) mutation [ 15 ]. The antihypertensive and organ protection effects of telmisartan or candesartan are greater in RGS2 -/- mice than in RGS2 +/+ mice [ 24 , 25 ]. Previous data support our results that the RGS2 (-391 C>G) genetic variation was associated with responses to ACE inhibitors and ARB but not with CCB.…”

“…In addition, telmisartan significantly improved the survival rates and suppressed vascular remodeling in an RGS2 -deficient mice model. Other studies suggest that Ang II causes a rapid and transient increase in RGS2 mRNA levels, which can be blocked by the calcium channel blocker (CCB) nifedipine[ 6 , 13 ]. Notably, one recent study observed that a cAMP-response element played a critical role in activating the RGS2 promoter, and the -867 to -367 bp region had an integral role in basal promoter activation [ 14 ].…”

Preclinical and Clinical Effects of RAS Inhibition with a Focus on Telmisartan

“…Angiotensin II is also involved in the formation of aneurysms [40], and telmisartan has been found to prevent their formation in two animal models. In mice deficient in regulator of G-protein signaling 2 (RGS2; a negative regulator of AT 1 receptors), telmisartan reduced the incidence of aneurysms [41]. In rat aortic tissue, telmisartan prevented abdominal aortic aneurysm progression independently of reducing BP, by inhibition of proteolysis, apoptosis, and inflammation [42].…”