Mahuang decoction targets fluid retention in heart failure with preserved ejection fraction.

Abstract

BACKGROUND: In heart failure with preserved ejection fraction (HFpEF), fluid volume overload constitutes a critical factor driving disease progression. Mahuang decoction (MHD), a traditional Chinese medicine with diaphoretic and diuretic properties, has shown potential in improving HFpEF, yet its mechanisms remain unclear. PURPOSE: This study aimed to explore the therapeutic effects of MHD on HFpEF and elucidate the mechanisms underlying its regulation of body fluid homeostasis. STUDY DESIGN: A HFpEF mouse model was induced by feeding male C57BL/6 J mice a high-fat diet combined with Nω-nitro L-arginine methyl ester (L-NAME) for 10 weeks, then received a 2-week MHD intervention. In vitro, AC16 cardiomyocytes and HK-2 renal tubular epithelial cells were employed for further validation. METHODS: The effects of MHD on HFpEF were evaluated by echocardiography, lung wet-dry ratio, exercise tolerance tests, sweating response assays, serum biomarkers, histopathology, and immunofluorescence staining. Molecular mechanisms were examined in vivo and in vitro using WB, RT-qPCR, ELISA and flow cytometry. In AC16 cells, pathway involvement was further probed using pharmacological inhibition of p38 MAPK (SB203580) and proprotein convertases (dec-RVKR-cmk). RESULTS: MHD significantly attenuated fluid retention, ameliorated cardiac remodeling and diastolic dysfunction. Mechanistically, MHD inhibited activation of p38 MAPK pathway, downregulated cardiac aquaporin (AQP) 4 and renal AQP2 to limit myocardial edema and water reabsorption, and upregulated dermal AQP5 to promote transcutaneous fluid excretion. Furthermore, MHD enhanced proprotein convertase subtilisin/kexin-6 (PCSK6) and Corin expression, thereby augmenting atrial natriuretic peptide (ANP)-mediated natriuresis and vascular remodeling. CONCLUSION: MHD ameliorated HFpEF through dual mechanisms involving p38 MAPK/AQPs regulation and PCSK6/Corin/ANP signaling, providing a promising approach for targeting the fluid retention in HFpEF therapy.