Isayama Yoko Shojima, Matsushima Shouji, Shinohara Keisuke, Isayama Koichi, Enzan Nobuyuki, Yamamoto Taishi, Sada Masashi, Miyake Ryo, Tsutsui Yoshitomo, Toyohara Takayuki, Nishimura Ryohei, Ikeda Yuki, Noda Eri, Otsuru Wataru, Tokumoto Shuya, Watanabe Masatsugu, Ikeda Masataka, Hashimoto Toru, Kinugawa Shintaro, Tsutsui Hiroyuki, Abe Kohtaro
Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
Division of Cardiovascular Medicine, Research Institute of Angiocardiology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
Hypertens Res. 2025 Sep 3. doi: 10.1038/s41440-025-02348-z.
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.
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