2. Academic Validation
  3. Inhibiting the MAPK pathway improves heart failure with preserved ejection fraction induced by salt-sensitive hypertension

Inhibiting the MAPK pathway improves heart failure with preserved ejection fraction induced by salt-sensitive hypertension

  • Biomed Pharmacother. 2023 Dec 5:170:115987. doi: 10.1016/j.biopha.2023.115987.
Shicheng Li 1,  Ying Shi 1,  Shanshan Yuan 2,  Jiangwen Ruan 1,  Honglian Pan 1,  Mengxiao Ma 1,  Guoxiu Huang 3,  Qingwei Ji 1,  You Zhong 4,  Tongmeng Jiang 5
Affiliations

Affiliations

  • 1 Department of Cardiology, The People's Hospital of Guangxi Zhuang Autonomous Region; Institute of Cardiovascular Sciences, Guangxi Academy of Medical Sciences, Nanning 530021, China.
  • 2 Department of Cardiology, Qingdao Hospital, University of Health and Rehabilitation Sciences (Qingdao Municipal Hospital), Qingdao 266011, China.
  • 3 Health Management Center, The People's Hospital of Guangxi Zhuang Autonomous Region; Guangxi Health Examination Center, Nanning 530021, China.
  • 4 Department of Cardiology, The People's Hospital of Guangxi Zhuang Autonomous Region; Institute of Cardiovascular Sciences, Guangxi Academy of Medical Sciences, Nanning 530021, China; Department of Cardiology, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing 100730, China. Electronic address: zhongyou2886@bjhmoh.cn.
  • 5 Key Laboratory of Hainan Trauma and Disaster Rescue, The First Affiliated Hospital of Hainan Medical University, Hainan Medical University, Haikou 571199, China; Engineering Research Center for Hainan Bio-Smart Materials and Bio-Medical Devices, Key Laboratory of Emergency and Trauma, Ministry of Education, Key Laboratory of Hainan Functional Materials and Molecular Imaging, College of Emergency and Trauma, Hainan Medical University, Haikou 571199, China. Electronic address: jiangtongmeng@hainmc.edu.cn.
PMID: 38056241 DOI: 10.1016/j.biopha.2023.115987
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.

Keywords

Doramapimod; HFpEF; Heart failure; MAPK pathway; Salt-sensitive hypertension.

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