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Published on: May 26, 2022
Inhibiting the MAPK pathway improves heart failure with preserved ejection fraction induced by salt-sensitive
Shicheng Li1, Ying Shi1, Shanshan Yuan2
1Department of Cardiology, The People's Hospital of Guangxi Zhuang Autonomous Region; Institute of Cardiovascular Sciences, Guangxi Academy of Medical Sciences, Nanning 530021, China.
Insights
A MAPK inhibitor, Doramapimod, shows promise in treating heart failure with preserved ejection fraction (HFpEF) caused by salt-sensitive hypertension. This study successfully modeled HFpEF in mice and demonstrated Doramapimod
Area of Science:
- Cardiovascular Physiology
- Molecular Biology
- Pharmacology
Background:
- Heart failure with preserved ejection fraction (HFpEF) constitutes nearly 50% of heart failure cases.
- Hypertension is a significant contributing factor to HFpEF.
- The role of the MAPK signaling pathway in HFpEF secondary to salt-sensitive hypertension requires further elucidation.
Purpose of the Study:
- To establish and validate a mouse model of HFpEF induced by salt-sensitive hypertension.
- To investigate the therapeutic potential of the MAPK inhibitor, Doramapimod, in this HFpEF model.
- To explore the effects of high salt concentrations on myogenic cells in vitro.
Main Methods:
- Establishment of a deoxycorticosterone acetate-salt (DOCA-salt) induced hypertension mouse model.
- Assessment of cardiac function via transthoracic echocardiography, blood pressure monitoring, running distance tests, and histological analysis.
- RNA sequencing (RNA-seq) to analyze gene expression, specifically the MAPK signaling pathway, and quantitative real-time PCR (qRTPCR) for validation.
Main Results:
- The DOCA-salt model successfully replicated HFpEF, characterized by left ventricular ejection fractions (LVEF) over 50%.
- Upregulation of the MAPK signaling pathway, hypertension, impaired exercise capacity, cardiac dysfunction, and increased fibrosis were observed in the HFpEF model.
- Doramapimod treatment improved blood pressure, reduced cardiomyocyte hypertrophy and myocardial fibrosis, and decreased heart failure biomarkers (GAL-3, LDHA, BNP).
Conclusions:
- The MAPK signaling pathway is implicated in the pathogenesis of salt-sensitive hypertension-induced HFpEF.
- Doramapimod demonstrates significant therapeutic efficacy in ameliorating cardiac dysfunction and pathological changes in this HFpEF model.
- MAPK inhibition represents a potential therapeutic strategy for managing HFpEF associated with salt-sensitive hypertension.
Abstract:
Heart failure (HF) preserved ejection fraction (HFpEF) accounts for almost 50% of HF, and hypertension is one of the pathogenies. The MAPK signaling pathway is closely linked to heart failure and hypertension; however, its function in HEpEF resulting from salt-sensitive hypertension is not well understood. In this work, a salt-sensitive hypertension-induced HEpEF model was established based on deoxycorticosterone acetate-salt (DOCA-salt) hypertension mice. The impact of the MAPK inhibitor (Doramapimod) on HEpEF induced by salt-sensitive hypertension was assessed through various measures, such as blood pressure, transthoracic echocardiography, running distance, and histological analysis, to determine its therapeutic effectiveness on cardiac function. In addition, the effects of high salt on myogenic cells were also evaluated in vitro using qRTPCR. The LV ejection fractions (LVEF) in DOCA-salt hypertension mice were over 50%, indicating that the salt-sensitive hypertension-induced HFpEF model was successful. RNA-seq revealed that the MAPK signaling pathway was upregulated in the HFpEF model compared with the normal mice, accompanied by hypertension, impaired running distance, restricted cardiac function, increased cross-sectional and fibrosis area, and upregulation of heart failure biomarkers, including GAL-3, LDHA and BNP. The application of Doramapimod could improve blood pressure, cardiomyocyte hypertrophy, and myocardial fibrosis, as well as decrease the aforementioned heart failure biomarkers. The qRTPCR results showed similar findings to these observations. Our findings suggest that the use of a MAPK inhibitor (Doramapimod) could be a potential treatment for salt-sensitive hypertension-induced HFpEF.
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