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

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.

This study aimed to explore the therapeutic effects of MHD on HFpEF and elucidate the mechanisms underlying its regulation of body fluid homeostasis.

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.

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).

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.

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.