Telmisartan, ramipril and their combination improve endothelial function in different tissues in a murine model of cholesterol‐induced atherosclerosis

Schlimmer, Nils; Kratz, Mario; Böhm, Michael; Baumhäkel, Magnus

doi:10.1111/j.1476-5381.2011.01267.x

Cited by 29 publications

(23 citation statements)

References 47 publications

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“…Based on the data showing the expression of ACE2 on the CC, we sought to evaluate if pharmacological increase of this enzyme would produce beneficial effects against injures induced by hypercholesterolemia. As previously observed [28,35], we found that ROS production was augmented in ApoE −/− mouse penis (Figure ), which was associated to an increased protein expression of NADPH oxidase (Figure ). Remarkably, the treatment with DIZE decreases ROS production in the CC of ApoE −/− mice to a comparable level of wild type mice (Figure A–D).…”

Section: Resultssupporting

confidence: 86%

Diminazene Protects Corpus Cavernosum Against Hypercholesterolemia-Induced Injury

Fraga‐Silva

Costa‐Fraga

Montecucco

et al. 2015

The Journal of Sexual Medicine

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Introduction. Angiotensin-converting enzyme 2 (ACE2) is a key enzyme of the renin angiotensin system, which breaks down angiotensin II and forms angiotensin-(1-7). In erectile tissues, it has been documented that angiotensin II contributes to the development of erectile dysfunction (ED), while treatment with angiotensin-(1-7) improves penile erection. However, the expression and function of ACE2 in erectile tissues have never been investigated. Aim. Here, we examined the expression of ACE2 in erectile tissues and its actions against hypercholesterolemia-induced corpus cavernosum (CC) injury. Methods. Hypercholesterolemic apolipoprotein E knockout (ApoE −/−) mice, a well-known model of ED, were treated with diminazene aceturate (DIZE), an ACE2 activator compound, or vehicle for 3 weeks. Reactive oxygen species (ROS), collagen content, and protein expression of ACE2, neuronal nitric oxide synthase (nNOS), endo-thelial nitric oxide synthase (eNOS), nicotinamide adenine dinucleotide phosphate-oxidase (NADPH) subunits were evaluated in the penis of DIZE-treated and untreated ApoE −/− mice. Functional studies were performed in CC strips. Main Outcome Measures. ACE2 expression and its role in modulating nitric oxide (NO)/ROS production and fibrosis within the CC of hypercholesterolemic mice were the main outcome measures. Results. ACE2 was expressed in smooth muscle and endothelial cells of mouse CC. Interestingly, ACE2 was downregulated in penis of hypercholesterolemic mice with ED, suggesting a protective role of ACE2 on the CC homeostasis. In accordance with that, pharmacological ACE2 activation by DIZE treatment reduced ROS production and NADPH oxidase expression, and elevated nNOS and eNOS expression and NO bioavailability in the penis of ApoE −/− mice. Additionally, DIZE decreased collagen content within the CC. These beneficial actions of DIZE on the CC were not accompanied by improvements in atherosclerotic plaque size or serum lipid profile. Conclusion. ACE2 is expressed in erectile tissue and its reduction is associated with hypercholesterolemia-induced ED. Additionally, treatment with DIZE improved hypercholesterolemia-induced CC injury, suggesting ACE2 as a potential target for treating ED. Fraga-Silva RA, Costa-Fraga FP, Montecucco F, Sturny M, Faye Y, Mach F, Pelli G, Shenoy V, da Silva RF, Raizada MK, Santos RAS, and Stergiopulos N. Diminazene protects corpus cavernosum against hypercholesterolemia-induced injury. J Sex Med 2015;12:289-302.

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Section: Resultssupporting

confidence: 86%

Diminazene Protects Corpus Cavernosum Against Hypercholesterolemia-Induced Injury

Fraga‐Silva

Costa‐Fraga

Montecucco

et al. 2015

The Journal of Sexual Medicine

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“…The relaxing effect of acetylcholine was abolished by adding N ω -nitro-L-arginine methyl ester (L-NAME, 1 μM). The presence of functional endothelium was verified by the ability of acetylcholine (10 μM) to induce more than 70% relaxation of rings precontracted with phenylephrine (1 μM) 25,26. Aortic rings without any response to acetylcholine (relaxation < 10%) were excluded from statistical analysis due to presumable damage of the endothelium.…”

Section: Methodsmentioning

confidence: 99%

Effect of 7-Difluoromethyl-5, 4΄-dimethoxygenistein on aorta atherosclerosis in hyperlipidemia ApoE-/- mice induced by a cholesterol-rich diet

Zhang¹,

Li²,

You³

et al. 2013

DDDT

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Purpose7-Difluoromethyl–5, 4′-dimethoxygenistein (DFMG), prepared by the difluoromethylation and alkylation of Genistein, is an active new chemical entity. Its anti-atherosclerosis effect was found in a series of studies in vitro. In this article, we explored and evaluated the anti-atherosclerosis effect via its protection of endothelial function in ApoE−/− mice that were fed a high-fat diet.MethodsFive C57BL/6J mice were selected as a control group and were fed a 1% high-fat diet (control group, n = 5). Five ApoE−/− mice that were fed a high-fat diet for 16 weeks were selected as the atherosclerosis model group (model group, n = 5). In the phase I study, 25 ApoE−/− mice were provided a prophylactic treatment with different drugs at the beginning of the 16 week high-fat diet: 5 mg/gk genistein (genistein 1 group, n = 5), 5 mg/kg lovastatin (lovastatin1 group, n = 5), 2.5 mg/kg DFMG (DFMG L1 group, n = 5), 5 mg/kg DFMG (DFMG M1 group, n = 5), and 10 mg/kg DFMG (DFMG H1 group, n = 5). In the phase II study, 25 atherosclerosis model, ApoE−/− mice were treated with different drugs and fed a high-fat diet for 16 weeks: 5 mg/gk genistein (genistein 2 group, n = 5), 5 mg/kg lovastatin (lovastatin 2 group, n = 5), 2.5 mg/kg DFMG (DFMG L2 group, n = 5), 5 mg/kg DFMG (DFMG M2 group, n = 5), and 10 mg/kg DFMG (DFMG H2 group, n = 5). The plasma levels of lipids, von Willebrand factor (vWF), and nitrite were compared between phases I and II. Endothelium-dependent relaxation (EDR), aortic lesion development, and quantification in thoracic aortas were measured during these two phase studies.ResultsCompared to the model group, the lipid and vWF plasma levels were significantly lower, the plasma nitrite levels were significantly higher, the fatty streaks of aortic lesions were significantly lower, and the endothelium dependent relaxation was significantly higher after both phase studies (P < 0.05). The DFMG supplementation led to significant plasma nitrite increment in all groups after both phase studies (P < 0.05). There were significantly decreased fatty streaks of aortic lesions in DFMG-prevented and DFMG-treated mice (P < 0.05). There was a significant increase in EDR in all prophylactic treatment groups and treatment groups (P < 0.05). We further demonstrated that the preventative effect was more obvious than the therapeutic effect.ConclusionOur results suggest that DFMG could work in prophylactic and therapeutic treatments for atherosclerosis development.

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“…In an animal model of hypertension‐induced ED, captopril reversed the impairment of erectile function . Accordingly, telmisartan and ramipril (ARBs and ACEi respectively), significantly improved the cavernosal endothelial function of hypercholesterolaemic mice via the reduction in oxidative stress . Moreover, in a rat model of diabetes‐induced ED, losartan treatment restored the impaired erectile function .…”

Section: Role Of Ang Ii/at1 Receptor Axis In Penile Erection Physiolomentioning

confidence: 97%

Pathophysiological role of the renin–angiotensin system on erectile dysfunction

Fraga‐Silva

Montecucco

Mach

et al. 2013

Eur J Clin Investigation

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Background The renin-angiotensin system (RAS) has been shown to play an active role within the erectile tissues. The aim of this narrative review is to summarize the literature addressing the pathophysiological role of RAS on erectile function. Additionally, we update evidence on recent findings on the role of the Ang-(1-7) and Mas receptor on the erectile function and its therapeutic potential for treating erectile dysfunction (ED).

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Telmisartan, ramipril and their combination improve endothelial function in different tissues in a murine model of cholesterol‐induced atherosclerosis

Cited by 29 publications

References 47 publications

Diminazene Protects Corpus Cavernosum Against Hypercholesterolemia-Induced Injury

Diminazene Protects Corpus Cavernosum Against Hypercholesterolemia-Induced Injury

Effect of 7-Difluoromethyl-5, 4΄-dimethoxygenistein on aorta atherosclerosis in hyperlipidemia ApoE-/- mice induced by a cholesterol-rich diet

Pathophysiological role of the renin–angiotensin system on erectile dysfunction

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