Telmisartan prevents aneurysm progression in the rat by inhibiting proteolysis, apoptosis and inflammation

Kaschina, Elena; Schrader, Frank Charles; Sommerfeld, Manuela; Kemnitz, Ulrich Rudolf; Grzesiak, Aleksandra; Krikov, Maxim; Unger, Thomas

doi:10.1097/hjh.0b013e328313e547

Cited by 53 publications

(41 citation statements)

References 40 publications

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“…13 In addition, activated caspase-9, the key initiator of the intrinsic pathway, was documented in experimental aneurysm, 14 further supporting the presence of mitochondrial-dependent apoptosis during aneurysm development. The integral relationship between SMC apoptosis and aneurysm is further demonstrated by studies in which apoptosis was attenuated by experimental approaches such as the removal of mast cells, 14 blockage of the angiotensin II (Ang II) signaling, 15 and inhibition of Rho GTPase. 16 However, whether and how SMC apoptosis contributes to aneurysm formation has not been directly addressed.…”

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confidence: 99%

Effects of Caspase Inhibitor on Angiotensin II-Induced Abdominal Aortic Aneurysm in Apolipoprotein E–Deficient Mice

Yamanouchi

Morgan

Kato

et al. 2010

ATVB

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Objective-The presence of apoptotic markers is a prominent histological feature of abdominal aortic aneurysm. To understand the role of apoptosis in the pathogenesis of this common vascular disease, we tested the effect of the pan-caspase inhibitor quinoline-Val-Asp-difluorophenoxymethylketone (Q-VD-OPh) on aneurysm formation using a mouse angiotensin II (Ang II) model. Methods and Results-Ang II in apolipoprotein E-deficient mice significantly induced medial cell apoptosis 3 days after infusion at the aortic region, eventually becoming aneurismal. A daily administration of 20 mg/kg per day Q-VD-OPh starting 6 hours before Ang II infusion reduced aneurysm incidence from 83.3% to 16.7% and maximal aortic diameter from 2.43Ϯ0.29 mm to 1.58Ϯ0.18 mm. The caspase inhibitor treated mice showed profoundly diminished levels of medial apoptosis and inflammation. In contrast, administration of Q-VD-OPh starting 7 days after Ang II infusion had no significant impact on aneurysm development. In vitro, media conditioned by Ang II-treated smooth muscle cells (SMCs) stimulated macrophage chemotaxis in a caspase-dependent manner. Inhibition of monocyte chemoattractant protein-1 (MCP-1) in the conditioned media via a neutralizing antibody completely blocked the ability of conditioned media to attract macrophages. Conclusion-These

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confidence: 99%

Effects of Caspase Inhibitor on Angiotensin II-Induced Abdominal Aortic Aneurysm in Apolipoprotein E–Deficient Mice

Yamanouchi

Morgan

Kato

et al. 2010

ATVB

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“…In Marfan syndrome, symptoms such as aneurysms and emphysema reflect excessive TGF-␤ signaling (13). Clinical (12,17) and animal (19,42) studies indicated that the ARBs telmisartan and losartan protected against the progression of aortic aneurysms. Telmisartan was reported to decrease TGF-␤ mRNA levels (43).…”

Section: Discussionmentioning

confidence: 99%

“…From a dental point of view, it is essential to determine the effect of ARBs on the progression of periodontitis. Among ARBs, telmisartan has the longest half-life of any ARB and has 3,000 times higher binding affinity to AT1 than to AT2 (18)(19)(20). In this study, we took advantage of the drug action of telmisartan and examined its effect on the experimental periodontitis model.…”

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Effect of Angiotensin II Receptor Blocker on Experimental Periodontitis in a Mouse Model of Marfan Syndrome

Suda

Moriyama

Ganburged³

2013

Infect Immun

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Marfan syndrome is an autosomal dominant disease characterized by aneurysm and dilatation of the aortic root, tall stature, and ectopia lentis. These manifestations reflect excessive signaling of transforming growth factor beta (TGF-␤). Moreover, cases are frequently associated with severe periodontitis, which is a chronic inflammation of the gingiva, periodontal ligament, and alveolar bone. Recently, angiotensin II receptor blockers (ARBs) were discovered to be an effective drug class that can prevent aortic aneurysm and dilation in Marfan syndrome by inhibiting TGF-␤ signaling. To investigate the effect of ARB on the progression of periodontitis, the application of a potent ARB, telmisartan, was examined in a mouse model of Marfan syndrome (Mg⌬). Six-week-old male heterozygous Mg⌬ and wild-type mice were challenged with Porphyromonas gingivalis, which causes chronic periodontitis, with and without telmisartan application. After infection, alveolar bone resorption was measured by micro-computed tomography (CT), and inflammatory cytokine levels were examined. Infection of Porphyromonas gingivalis induced alveolar bone resorption in both Mg⌬ and wild-type mice. The amount of resorption was significantly larger in the former than the latter. Immunoarray and enzyme-linked immunosorbent assay (ELISA) analyses demonstrated that interleukin-17 (IL-17) and tumor necrosis factor alpha (TNF-␣) levels were significantly higher in infected Mg⌬ mice than infected wild-type mice. Telmisartan treatment significantly suppressed the alveolar bone resorption of infected Mg⌬ mice. Telmisartan also significantly decreased levels of TGF-␤, IL-17, and TNF-␣ in infected Mg⌬ mice to levels seen in infected wild-type mice. This study suggests that ARB can prevent the severe periodontitis frequently seen in Marfan syndrome.

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“…Some reports have shown that telmisartan and another ARB, valsartan, prevent vascular remodeling through inhibition of oxidative stress, inflammation and degradation of the extracellular matrix independent of their antihypertensive effects. 20,[24][25][26] Heximer et al 9 have reported that responsiveness to another ARB, candesartan, is more sensitive in Rgs2 À/À mice than Rgs2 +/+ mice with regard to its antihypertensive and organ protection effects. Thus, vascular protective effects through inhibition of oxidative stress by low-dose ARB may be exaggerated in Rgs2 À/À mice as a result of its antagonism for excessive AT 1 R signaling.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2010

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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.

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Telmisartan prevents aneurysm progression in the rat by inhibiting proteolysis, apoptosis and inflammation

Abstract: The angiotensin II type 1 receptor antagonist, telmisartan, prevents abdominal aortic aneurysm progression independently of blood pressure reduction by inhibiting proteolysis, apoptosis and inflammation in aortic tissue.

Cited by 53 publications

References 40 publications

Effects of Caspase Inhibitor on Angiotensin II-Induced Abdominal Aortic Aneurysm in Apolipoprotein E–Deficient Mice

Effects of Caspase Inhibitor on Angiotensin II-Induced Abdominal Aortic Aneurysm in Apolipoprotein E–Deficient Mice

Effect of Angiotensin II Receptor Blocker on Experimental Periodontitis in a Mouse Model of Marfan Syndrome

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

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