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

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.