Original article
The angiotensin receptor blocker, telmisartan, reduces and stabilizes atherosclerosis in ApoE and AT1aR double deficient mice

https://doi.org/10.1016/j.biopha.2010.09.014Get rights and content

Abstract

The renin-angiotensin system (RAS) plays critical roles in the pathogenesis of atherosclerosis. Clinical studies demonstrate that pharmacological blockade of RAS with Angiotensin II type 1 receptor (AT1R) blockers (ARBs) is effective in the treatment of patients with cardiovascular diseases. Recent studies reported that telmisartan, an ARB, has a partial agonistic effect on peroxisome proliferator-activated receptor-gamma (PPAR-γ). The role of PPAR-γ-mediated signaling has been implicated in regulation of not only metabolic disorders but also atherosclerosis. Here, we investigated the effects of telmisartan, which is not related to AT1R blockade, using AT1aR and apolipoprotein E (ApoE) double-deficient (ApoE−/−AT1R−/−) mice in vivo. Both genetic ablation of AT1R in ApoE-deficient (ApoE−/−) mice and administration of telmisartan (10 mg/kg/day) to ApoE−/− mice for 20 weeks reduced the development of atherosclerosis (P < 0.05, respectively). Telmisartan decreased lipid deposition (P < 0.01) and increased collagen contents (P < 0.05) in plaques in ApoE−/− mice. Administration of telmisartan to ApoE−/−AT1aR−/− mice also inhibited the progression of atherosclerosis in aorta (P < 0.05) even in mice, which have no AT1aR genetically. Moreover, in these mice, telmisartan decreased macrophage accumulation and lipid deposition, and increased collagen contents in plaques in aortic root (P < 0.05, respectively), indicating stabilization of plaques. Telmisartan-treated ApoE−/−AT1aR−/− mice showed lower body weight and higher plasma high-density lipoprotein levels compared with vehicle-treated mice (P < 0.05, respectively). Telmisartan lowered systolic and diastolic blood pressure in ApoE−/−AT1aR−/− mice (P < 0.01). These results suggest that telmisartan has protective effects on the development of atherosclerosis and metabolic disorders beyond AT1R blockade in ApoE-deficient mice.

Introduction

Atherosclerosis is one of the chronic inflammatory diseases [1]. Many factors cause atherosclerosis, where the renin-angiotensin system (RAS) plays critical roles in the pathogenesis of atherosclerosis by promoting a series of coordinated cellular and molecular events observed in lesions [2], [3]. Recent clinical trials suggest that pharmacological blockade of RAS with Angiotensin II type 1 receptor (AT1R) blockers (ARBs) is effective in the treatment of patients with cardiovascular diseases [4]. These drugs exert various favorable effects on endothelial function [5], [6], cardiac function [7], [8], cerebral vascular function [9], [10] and renal function [11] by inhibiting RAS other than blood pressure lowering effect. Accumulating evidence suggests the interaction between RAS and metabolic systems [12], [13]. Actually, several studies demonstrated that AT1R blockade has additional therapeutic benefits in the metabolic syndrome and other obesity-related disorders beyond blood pressure lowering effect [14], [15].

Recent reports suggest that telmisartan, an ARB, functions as a partial agonist of peroxisome proliferator-activated receptor-γ (PPAR-γ), leading to improvement of glucose and lipid profiles in vivo and in vitro [16], [17], [18]. Benson et al. reported that none of the other commercially available angiotensin II receptor antagonists appeared to activate PPAR-γ when tested at concentrations typically achieved in plasma with conventional oral dosing [16]. PPAR-γ agonist, including pioglitazone and rosiglitazone, improve insulin resistance [19]. Furthermore, accumulating evidence suggests that activators of PPAR-γ exert anti-inflammatory, anti-oxidative and anti-proliferative effects on vascular wall cells, thus decreasing the risks for atherosclerosis [20]. Telmisartan is hoped to have the potential to treat both hemodynamic and biochemical features in patients with metabolic syndromes and to provide unique opportunities for the prevention and treatment of diabetes and cardiovascular disease in high-risk populations by simultaneously blocking the angiotensin II receptor and activating PPAR-γ [16], [21].

Here, we investigated the additional effects of telmisartan that is not related to AT1R blockade by administrating telmisartan to AT1aR deficient hypercholesterolemic mice. Administration of telmisartan prevented the development of atherosclerosis even in AT1aR deficient animals. Telmisartan also improved metabolic parameters including body weight, serum high-density lipoprotein (HDL) levels, and blood pressure in these mice. Telmisartan has atheroptoective effects that are not related to the RAS.

Section snippets

Animals and drug administration

ApoE−/− mice (C57BL/6J background) were originally purchased from Jackson Laboratory. AT1aR knockout (AT1R−/−) mice (C57BL/6J background) were previously described [3]. We generated double knockout mice deficient of ApoE and AT1aR by cross-breeding ApoE−/− mice and AT1aR−/− mice. All procedures involving experimental animals were performed in accordance with protocols approved by the institutional committee for animal research of The University of Tokyo and complied with the Guide for the Care

Effects of telmisartan on atherosclerotic plaque formation in ApoE−/− mice

We compared atherosclerotic lesion progression between male ApoE−/−AT1aR+/+ mice (n = 4) and ApoE−/−AT1aR−/− mice (n = 4) fed normal chow at 24-weeks of age. Result of en face Sudan IV staining demonstrated that genetic AT1aR disruption significantly reduced development of atherosclerosis in ApoE−/− mice (Sudan IV-positive area: 20.8 ± 3.6% versus 10.7 ± 1.9%, P < 0.05, Fig. 1A). Next, 10 mg/kg/day telmisartan (n = 4) or 30 mg/kg/day hydralazine (n = 3) was administered to six-week-old male ApoE−/− mice fed a

Discussion

In this study, the result of genetic ablation of AT1aR in ApoE−/− mice demonstrated that AT1aR plays critical roles in atherogenesis in hypercholesterolemic animals. We also demonstrated that telmisartan reduces development of atherosclerosis and increases stability of plaques not only in ApoE−/− mice but also in ApoE−/−AT1aR−/− mice, which have no AT1aR genetically. Telmisartan is a unique ARB with selective PPARγ-activating activity. Our findings suggest that telmisartan could exert

Conflict of interest statement

None.

Sources of funding

This study was supported in part by the Program for Promotion of Basic and Applied Researches for Innovations in Bio-oriented Industry and by grants from the Ministry of Education, Culture, Sports, Science and Technology (Knowledge Cluster and Scientific Research on Innovative Areas) and the Ministry of Health, Labor and Welfare of Japan.

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