Goreisan attenuates cardiac hypertrophy and diastolic dysfunction in heart failure with preserved ejection fraction induced by HFD/L-NAME via regulation of ICAT-β-catenin/ERK axis

Yoko Shojima Isayama; Shouji Matsushima; Keisuke Shinohara; Koichi Isayama; Nobuyuki Enzan; Taishi Yamamoto; Masashi Sada; Ryo Miyake; Yoshitomo Tsutsui; Takayuki Toyohara; Ryohei Nishimura; Yuki Ikeda; Eri Noda; Wataru Otsuru; Shuya Tokumoto; Masatsugu Watanabe; Masataka Ikeda; Toru Hashimoto; Shintaro Kinugawa; Hiroyuki Tsutsui; Kohtaro Abe

doi:10.1038/s41440-025-02348-z

Goreisan attenuates cardiac hypertrophy and diastolic dysfunction in heart failure with preserved ejection fraction induced by HFD/L-NAME via regulation of ICAT-β-catenin/ERK axis

Hypertens Res. 2025 Nov;48(11):2882-2896. doi: 10.1038/s41440-025-02348-z. Epub 2025 Sep 3.

Authors

Yoko Shojima Isayama^{1

2}, Shouji Matsushima^{3

4}, Keisuke Shinohara^{1

2}, Koichi Isayama^{1

2}, Nobuyuki Enzan^{1

2}, Taishi Yamamoto^{1

2}, Masashi Sada^{1

2}, Ryo Miyake^{1

2}, Yoshitomo Tsutsui^{1

2}, Takayuki Toyohara^{1

2}, Ryohei Nishimura^{1

2}, Yuki Ikeda^{1

2}, Eri Noda^{1

2}, Wataru Otsuru^{1

2}, Shuya Tokumoto^{1

2}, Masatsugu Watanabe^{1

2

5}, Masataka Ikeda^{1

2}, Toru Hashimoto^{1

2}, Shintaro Kinugawa^{1

2}, Hiroyuki Tsutsui^{1

2

6}, Kohtaro Abe^{1

2}

Affiliations

¹ Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
² Division of Cardiovascular Medicine, Research Institute of Angiocardiology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
³ Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan. matsushima.shoji.056@m.kyushu-u.ac.jp.
⁴ Division of Cardiovascular Medicine, Research Institute of Angiocardiology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan. matsushima.shoji.056@m.kyushu-u.ac.jp.
⁵ Department of Anesthesiology and Critical Care Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
⁶ School of Medicine and Graduate School, International University of Health and Welfare, Fukuoka, Japan.

Abstract

Heart failure with preserved ejection fraction (HFpEF), characterized by cardiac hypertrophy and diastolic dysfunction, is increasing worldwide. Goreisan (GRS) is a traditional herbal formulation; its component attenuates cardiomyocyte hypertrophy. This study aimed to investigate the effect of GRS on the pathophysiology of HFpEF. Administration of a high fat diet (HFD, 60% fat) and N-nitro-L-arginine methylester (L-NAME, 0.5 g/L in drinking water) increased heart and lung weights in C57BL/6 mice and GRS (5.9 mg/kcal) reduced them without changes in blood pressure. GRS attenuated HFD/L-NAME-induced increases in left ventricular wall thickness and E/A and E/E', indices of diastolic dysfunction. GRS decreased cardiomyocyte cross-sectional area in HFD/L-NAME-treated mice. Mechanistically, it suppressed the phosphorylation of mitogen-activated protein kinases (MAPKs), such as extracellular signal-regulated kinase (ERK), in HFD/L-NAME-treated hearts. In addition, liquid chromatography/mass spectrometry demonstrated that HFD/L-NAME decreased and GRS increased 73 proteins in the heart. Among them, GRS prevented HFD/L-NAME-induced decrease in inhibitor of β-catenin and T-cell factor (ICAT), a negative regulator of cardiac hypertrophy. Consistently, β-catenin, an ICAT target, exhibited the opposite change. In in vitro experiments, GRS directly decreased β-catenin in isoproterenol (ISO)-treated cardiomyocytes, accompanied by a decrease in cardiomyocyte surface area. Overexpression of ICAT also suppressed ISO-induced increases in β-catenin, phosphorylated ERK, and cardiomyocyte surface area. Among GRS ingredients, cinnamaldehyde and alisol B 23-acetate attenuated ISO-induced increases in β-catenin and cardiomyocyte surface area. In conclusion, GRS attenuates cardiac hypertrophy and diastolic dysfunction via ICAT-β-catenin/ERK axis. GRS is a potential herbal formulation for the treatment of HFpEF.

Keywords: Goreisan; cardiac hypertrophy; diastolic dysfunction; heart failure with preserved ejection fraction.

MeSH terms

Animals
Cardiomegaly* / drug therapy
Cardiomegaly* / metabolism
Cardiomegaly* / physiopathology
Diastole / drug effects
Diet, High-Fat
Drugs, Chinese Herbal* / pharmacology
Drugs, Chinese Herbal* / therapeutic use
Extracellular Signal-Regulated MAP Kinases / metabolism
Heart Failure* / drug therapy
Heart Failure* / metabolism
Heart Failure* / physiopathology
MAP Kinase Signaling System / drug effects
Male
Mice
Mice, Inbred C57BL
Myocytes, Cardiac / drug effects
NG-Nitroarginine Methyl Ester / pharmacology
Stroke Volume / drug effects
beta Catenin / metabolism

Substances

NG-Nitroarginine Methyl Ester
beta Catenin
Drugs, Chinese Herbal
Extracellular Signal-Regulated MAP Kinases