Effect of LCZ696, a dual angiotensin receptor neprilysin inhibitor, on isoproterenol-induced cardiac hypertrophy, fibrosis, and hemodynamic change in rats

Miyoshi, Toru; Nakamura, Kazufumi; Miura, Daiji; Yoshida, Masashi; Saito, Yukihiro; Akagi, Satoshi; Ohno, Yuko; Kondo, Megumi; Ito, Hiroshi

doi:10.5603/cj.a2018.0048

Cited by 18 publications

(20 citation statements)

References 24 publications

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“…cDNA was synthesised using the Prime Script RT reagent kit (Takara) following the manufacturer's instructions. Real-time qPCR was performed using the TaqMan Universal PCR Master Mix (Applied Biosystems, CA) and an Applied Biosystems 7500 Fast Real-Time PCR System (Applied Biosystems) 26 . All mRNA-specific labelled primers were purchased from Applied Biosystems and detected cDNA from the following genes: Il1b (Mm00434228_m1), Il6 (Mm00446190_ m1), and Cd44 (Mm01277161_m1).…”

Section: Murine Model Of Bapn/ang Ii-induced Aortic Dissection Eightmentioning

confidence: 99%

Deficiency of CD44 prevents thoracic aortic dissection in a murine model

Hatipoğlu

Miyoshi

Yonezawa

et al. 2020

Sci Rep

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Thoracic aortic dissection (TAD) is a life-threatening vascular disease. We showed that CD44, a widely distributed cell surface adhesion molecule, has an important role in inflammation. In this study, we examined the role of CD44 in the development of TAD. TAD was induced by the continuous infusion of β-aminopropionitrile (BAPN), a lysyl oxidase inhibitor, and angiotensin II (AngII) for 7 days in wild type (WT) mice and CD44 deficient (CD44 -/-) mice. The incidence of TAD in CD44 -/mice was significantly reduced compared with WT mice (44% and 6%, p < 0.01). Next, to evaluate the initial changes, aortic tissues at 24 hours after BAPN/AngII infusion were examined. Neutrophil accumulation into thoracic aortic adventitia in CD44 -/mice was significantly decreased compared with that in WT mice (5.7 ± 0.3% and 1.6 ± 0.4%, p < 0.01). In addition, BAPN/AngII induced interleukin-6, interleukin-1β, matrix metalloproteinase-2 and matrix metalloproteinase-9 in WT mice, all of which were significantly reduced in CD44 −/− mice (all p < 0.01). In vitro transmigration of neutrophils from CD44 −/− mice through an endothelial monolayer was significantly decreased by 18% compared with WT mice (p < 0.01). Our findings indicate that CD44 has a critical role in TAD development in association with neutrophil infiltration into adventitia. open Scientific RepoRtS | (2020) 10:6869 | https://doi.org/10.1038/s41598-020-63824-9www.nature.com/scientificreports www.nature.com/scientificreports/ routes of administration including oral gavage 7,14 , subcutaneous osmotic pump infusion 15 , and subcutaneous injection 16,17 , have previously been established. In the current study, we investigated the role of CD44 in TAD induced by BAPN/AngII by comparing wild type (WT) and CD44 deficient (CD44 −/− ) mice. Results CD44 deficiency in mice decreases rates of aortic dissection.To investigate the effects of CD44 deficiency on the development of aortic dissection, WT and CD44 −/− mice were administered saline or BAPN/AngII for 7 days (Fig. 1). Saline-treated WT and CD44 −/− mice were used as controls. A slight increase in blood pressure after treatment with BAPN/AngII was observed in WT and CD44 −/− mice (Supplemental Fig. 1). Treatment with BAPN/AngII led to thoracic and abdominal aortic dissection (the presence of an intramural thrombus) and rupture. Figure 2A shows a representative image of TAD (white arrow). Histological analyses in thoracic aortae showed that intramural haematoma (black arrow) and degradation of elastin (yellow arrow) were present in the dissection area (Fig. 2B). The incidence of aortic dissection in BAPN/AngII-treated CD44 −/− mice was approximately 0.4 times as high as the incidence in BAPN/AngII-treated WT mice (69% and 26%, p = 0.01) (Fig. 2C). Furthermore, the incidence of TAD after BAPN/AngII treatment was significantly reduced in CD44 −/− mice compared with WT mice (44% and 6%, p < 0.01). However, no difference in the incidence of abdominal aortic dissection was observed (25% and 20%, p = 0.76) ( Fig. 2D). Scientific RepoRtS...

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Section: Murine Model Of Bapn/ang Ii-induced Aortic Dissection Eightmentioning

confidence: 99%

Deficiency of CD44 prevents thoracic aortic dissection in a murine model

Hatipoğlu

Miyoshi

Yonezawa

et al. 2020

Sci Rep

Self Cite

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“…On the one hand, valsartan can block angiotensin type 1 receptor (AT1), inhibit the release of Ang II dependent aldosterone, and antagonize RAAS. It is beneficial to slow down the development of heart failure by reducing sympathetic nerve excitability and myocardial oxygen consumption, improving hemodynamics, and inhibiting myocardial fibrosis [ 14 ]. On the other hand, the degradation of natriuretic peptide system by enkephalinase (NEP) was inhibited by sacubitril, thus enhancing the natriuretic peptide system.…”

Section: Introductionmentioning

confidence: 99%

Effects and Safety of Sacubitril/Valsartan for Patients with Myocardial Infarction: A Systematic Review and Meta-Analysis

Ding

Han

2022

Journal of Healthcare Engineering

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Patients who develop heart failure (HF) after an acute myocardial infarction (AMI) are at higher risk of adverse fatal and nonfatal outcomes. Studies have shown sacubitril/valsartan can further reduce the risk of cardiovascular death or hospitalization for heart failure by 20% compared with enalapril. At the same time, its tolerance and safety are better. However, the current evidence regarding the efficacy of sacubitril/valsartan in patients with heart failure after acute myocardial infarction is controversial. To assess the effect of sacubitril/valsartan on heart failure after acute myocardial infarction, we conducted a systematic review of the literature and a meta-analysis of existing randomized clinical trials. Meta-analysis of randomized controlled trails is used where data are collected from PubMed, the Cochrane library, Embase, and Web of Science. Data about sacubitril/valsartan were available from 5 studies. Forest plots showed that the sacubitril/valsartan group had a 299% higher value of sacubitril/valsartan to the control group (MD = 2.99%, 95% CI: 2.01, 3.96, I2 = 78%, P < 0.00001 , Figure 2), and the difference was statistically significant. Forest plots showed that the sacubitril/valsartan group had a 531% lower value of LVEF to the control group (MD = −5.31%, 95% CI: −7.36, −3.26, I2 = 91%, P < 0.00001 , Figure 2), and the difference was statistically significant. Forest plots showed that the sacubitril/valsartan group had a 133% lower value of NT-proBNP to the control group (MD = −1.33%, 95% CI: −1.54, −1.12, I2 = 96%, P < 0.00001 , Figure 3). Forest plots showed that the sacubitril/valsartan group had a 49% lower risk of heart failure to the control group (MD = 0.49, 95% CI: 0.27, 0.89, I2 = 0%, P = 0.02 , Figure 3). The patients in experimental showed an obviously lower OR of MACE (OR = 0.47, 95% CI: 0.27, 0.82, P = 0.007 , Figure 3). The data were statistically significant. We have observed that for patients with heart failure after acute myocardial infarction, early administration of sacubitril/valsartan can significantly reduce the incidence of heart rate, left ventricular ejection fraction, NT-proBNP, and MACE. Our meta-analysis suggests that taking sacubitril/valsartan is relatively safe and effective, especially if started early after acute myocardial infarction.

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“…Furthermore, LCZ696 treatment inhibited cardiac hypertrophy, fibrosis, and vasculopathy in a rat model of chronic kidney disease [5]. However, LCZ696 treatment improved isoproterenol-induced cardiac fibrosis, but not hypertrophy, in rats [6]. e effects of LCZ696 on pressure overload-induced cardiac hypertrophy remain unclear, and the possible potential mechanisms are unknown.…”

Section: Introductionmentioning

confidence: 99%

LCZ696, an Angiotensin Receptor-Neprilysin Inhibitor, Improves Cardiac Hypertrophy and Fibrosis and Cardiac Lymphatic Remodeling in Transverse Aortic Constriction Model Mice

Zhao

Liu

et al. 2020

BioMed Research International

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Cardiac hypertrophy and ventricular remodeling following heart failure are important causes of high mortality in heart disease patients. The cardiac lymphatic system has been associated with limited research, but it plays an important role in the improvement of myocardial edema and the promotion of fluid balance. LCZ696 is a novel combination of angiotensin and neprilysin inhibitors. Here, we studied the role played by LCZ696 during transverse aortic constriction (TAC) induced cardiac hypertrophy and changes in the lymphatic system. Mice undergoing aortic coarctation were constructed to represent a cardiac hypertrophy model and then divided into random groups that either received treatment with LCZ696 (60 mg/kg/d) or no treatment. Cardiac ultrasonography was used to detect cardiac function, and hematoxylin and eosin (H&E) and Masson staining were used to detect myocardial hypertrophy and fibrosis. The proinflammatory factors interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-α (TNF-α) were detected in the blood and heart tissues of mice. The protein expression levels of lymphatic-specific markers, such as vascular endothelial growth factor C (VEGF-C), VEGF receptor 3 (VEGFR3), and lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1) were detected in mouse heart tissues. We also examined the colocalization of lymphatic vessels and macrophages by immunofluorescence. The results showed that LCZ696 significantly improved heart dysfunction, cardiac hypertrophy, and fibrosis and inhibited the expression of proinflammatory factors IL-6, IL-1β, and TNF-α in the circulating blood and heart tissues of mice. LCZ696 also decreased the protein expression levels of VEGF-C, VEGFR3, and LYVE-1 in mouse heart tissues, ameliorated the transport load of lymphatic vessels to macrophages, and improved the remodeling of the lymphatic system in the hypertrophic cardiomyopathy model induced by TAC.

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Effect of LCZ696, a dual angiotensin receptor neprilysin inhibitor, on isoproterenol-induced cardiac hypertrophy, fibrosis, and hemodynamic change in rats

Abstract: LCZ696 improves cardiac fibrosis, but not hypertrophy, caused by continuous exposure to ISO in rats.

Cited by 18 publications

References 24 publications

Deficiency of CD44 prevents thoracic aortic dissection in a murine model

Deficiency of CD44 prevents thoracic aortic dissection in a murine model

Effects and Safety of Sacubitril/Valsartan for Patients with Myocardial Infarction: A Systematic Review and Meta-Analysis

LCZ696, an Angiotensin Receptor-Neprilysin Inhibitor, Improves Cardiac Hypertrophy and Fibrosis and Cardiac Lymphatic Remodeling in Transverse Aortic Constriction Model Mice

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