Sacubitril/Valsartan Improves Diastolic Function But Not Skeletal Muscle Function in a Rat Model of HFpEF

Schauer, Antje; Adams, Volker; Augstein, Antje; Jannasch, Anett; Draskowski, Runa; Kirchhoff, Virginia; Goto, Kosaku; Mittag, Jeniffer; Galli, Roberta; Männel, Anita; Barthel, Peggy; Linke, Axel; Winzer, Ephraim B

doi:10.3390/ijms22073570

Cited by 29 publications

(40 citation statements)

References 45 publications

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“…The observed effects on myocardial and SKM function are probably independent of modulating hypertension and glucose concentration ( Table 1). This in accordance with an earlier study by our group were the application of Sacubitril/Valsartan to ZSF1‐obese animals lowered blood pressure but had no effect on SKM atrophy/function 24 . Also, in a separate mouse study, we found that MyoMed‐205 had no significant effects on basal glucose or oral glucose tolerance 45 .…”

Section: Discussionsupporting

confidence: 92%

“…In the present study, we tested if this compound class can also prevent SKM atrophy in HFpEF. For this, we selected the ZSF1 rat model that is commonly used to investigate interventional strategies in HFpEF 3,24,25 . As compound, we selected MyoMed‐205 that has improved serum stability when compared with initial lead compound ID#704946 21,22 (see Supporting Information, Figure S1).…”

Section: Introductionmentioning

confidence: 99%

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Targeting MuRF1 by small molecules in a HFpEF rat model improves myocardial diastolic function and skeletal muscle contractility

Adams

Schauer

Augstein

et al. 2022

J cachexia sarcopenia muscle

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Background About half of heart failure (HF) patients, while having preserved left ventricular function, suffer from diastolic dysfunction (so-called HFpEF). No specific therapeutics are available for HFpEF in contrast to HF where reduced ejection fractions (HFrEF) can be treated pharmacologically. Myocardial titin filament stiffening, endothelial dysfunction, and skeletal muscle (SKM) myopathy are suspected to contribute to HFpEF genesis. We previously described small molecules interfering with MuRF1 target recognition thereby attenuating SKM myopathy and dysfunction in HFrEF animal models. The aim of the present study was to test the efficacy of one small molecule (MyoMed-205) in HFpEF and to describe molecular changes elicited by MyoMed-205. Methods Twenty-week-old female obese ZSF1 rats received the MuRF1 inhibitor MyoMed-205 for 12 weeks; a comparison was made to age-matched untreated ZSF1-lean (healthy) and obese rats as controls. LV (left ventricle) function was assessed by echocardiography and by invasive haemodynamic measurements until week 32. At week 32, SKM and endothelial functions were measured and tissues collected for molecular analyses. Proteome-wide analysis followed by WBs and RT-PCR was applied to identify specific genes and affected molecular pathways. MuRF1 knockout mice (MuRF1-KO) SKM tissues were included to validate MuRF1-specificity. Results By week 32, untreated obese rats had normal LV ejection fraction but augmented E/e′ ratios and increased end diastolic pressure and myocardial fibrosis, all typical features of HFpEF. Furthermore, SKM myopathy (both atrophy and force loss) and endothelial dysfunction were detected. In contrast, MyoMed-205 treated rats had markedly improved diastolic function, less myocardial fibrosis, reduced SKM myopathy, and increased SKM function. SKM extracts from MyoMed-205 treated rats had reduced MuRF1 content and lowered total muscle protein ubiquitination. In addition, proteomic profiling identified eight proteins to respond specifically to MyoMed-205 treatment. Five out of these eight proteins are involved in mitochondrial metabolism, dynamics, or autophagy. Consistent with the mitochondria being a MyoMed-205 target, the synthesis of mitochondrial respiratory chain complexes I + II was increased in treated rats. MuRF1-KO SKM controls also had elevated mitochondrial complex I and II activities, also suggesting mitochondrial activity regulation by MuRF1. Conclusions MyoMed-205 improved myocardial diastolic function and prevented SKM atrophy/function in the ZSF1 animal model of HFpEF. Mechanistically, SKM benefited from an attenuated ubiquitin proteasome system and augmented synthesis/activity of proteins of the mitochondrial respiratory chain while the myocardium seemed to benefit from reduced titin modifications and fibrosis.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Targeting MuRF1 by small molecules in a HFpEF rat model improves myocardial diastolic function and skeletal muscle contractility

Adams

Schauer

Augstein

et al. 2022

J cachexia sarcopenia muscle

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“…Sacubitril/Valsartan (LCZ696) is a new superstar in the management of heart failure and hypertension. Two recently-released independent studies showed that sacubitril/valsartan inhibits the progress of diastolic dysfunction and arterial stiffness to HFpEF in rat models ( 44 , 45 ). However, clinical trials are needed to verify the effects of sacubitril/valsartan on HFpEF patients.…”

Section: Does Treatment For Arterial Stiffness Benefit In Hfpef?mentioning

confidence: 99%

Association Between Arterial Stiffness and Heart Failure With Preserved Ejection Fraction

Chen

Liu

2021

Front. Cardiovasc. Med.

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Cardiovascular diseases are the leading cause of mortality in the world. Heart failure with preserved ejection fraction (HFpEF) accounts for about half of all heart failure. Unfortunately, the mechanisms of HFpEF are still unclear, leading to little progress of effective treatment of HFpEF. Arterial stiffness is the decrement of arterial compliance. The media of large arteries degenerate in both physiological and pathological conditions. Many studies have proven that arterial stiffness is an independent risk factor for cardiovascular disorders including diastolic dysfunction. In this perspective, we discussed if arterial stiffness is related to HFpEF, and how does arterial stiffness contribute to HFpEF. Finally, we briefly summarized current treatment strategies on arterial stiffness and HFpEF. Though some new drugs were developed, the safety and effectiveness were not adequately assessed. New pharmacologic treatment for arterial stiffness and HFpEF are urgently needed.

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“…Obese diabetic Zucker fatty/spontaneously hypertensive HF F1 hybrid (ZSF1-OB) rats exhibit spontaneous type 2 diabetes, diabetic kidney disease, hypertension, hyperlipidemia, obesity and metabolic syndrome features ( Hohendanner et al, 2018 ; Davila et al, 2019 ; Leite et al, 2019 ; Park et al, 2020 ; Schauer et al, 2020 ). A number of studies demonstrated that ZSF1-OB had cardiac manifestations such as normal LVEF, increased E/A, left atrial enlargement, elevated LVEDP, upward EDPVR curve, and reduced activity tolerance ( Leite et al, 2019 ; Satoh et al, 2021 ; Schauer et al, 2021 ). In addition, compared with lean ZSF1(ZSF1-LN) in the control group, ZSF1-OB displayed significant aortic remodeling and arterial collagen deposition, central vascular remodeling, which aggravated the hypertensive phenotype and promoted HFpEF.…”

Section: Small Animal Models Of Hfpefmentioning

confidence: 99%

Mimicking Metabolic Disturbance in Establishing Animal Models of Heart Failure With Preserved Ejection Fraction

Xia

et al. 2022

Front. Physiol.

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Heart failure (HF), the terminal state of different heart diseases, imposed a significant health care burden worldwide. It is the last battlefield in dealing with cardiovascular diseases. HF with preserved ejection fraction (HFpEF) is a type of HF in which the symptoms and signs of HF are mainly ascribed to diastolic dysfunction of left ventricle, whereas systolic function is normal or near-normal. Compared to HF with reduced ejection fraction (HFrEF), the diagnosis and treatment of HFpEF have made limited progress, partly due to the lack of suitable animal models for translational studies in the past. Given metabolic disturbance and inflammatory burden contribute to HFpEF pathogenesis, recent years have witnessed emerging studies focusing on construction of animal models with HFpEF phenotype by mimicking metabolic disorders. These models prefer to recapitulate the metabolic disorders and endothelial dysfunction, leading to the more detailed understanding of the entity. In this review, we summarize the currently available animal models of HFpEF with metabolic disorders, as well as their advantages and disadvantages as tools for translational studies.

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Sacubitril/Valsartan Improves Diastolic Function But Not Skeletal Muscle Function in a Rat Model of HFpEF

Cited by 29 publications

References 45 publications

Targeting MuRF1 by small molecules in a HFpEF rat model improves myocardial diastolic function and skeletal muscle contractility

Targeting MuRF1 by small molecules in a HFpEF rat model improves myocardial diastolic function and skeletal muscle contractility

Association Between Arterial Stiffness and Heart Failure With Preserved Ejection Fraction

Mimicking Metabolic Disturbance in Establishing Animal Models of Heart Failure With Preserved Ejection Fraction

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