Unveiling zhenwu decoction: A promising remedy for hypertensive heart failure via MAPKs/STAT2-NLRC5 pathway.

Hypertension is an important risk factor for heart failure. Zhenwu Decoction (ZWD) is a classical Chinese medicinal recipe that has been extensively used to manage cardiovascular disorders throughout history. However, the fundamental processes involved in its effects were not clear. In this study, we investigated the effects of ZWD on Ang II-induced cardiac remodeling and heart failure. A hypertensive heart failure (HF) mice model was established via the micro-osmotic pump infusion of Ang II in C57BL/6 mice for 4 weeks. After two weeks of infusion, ZWD and valsartan were administered intragastrically for another two weeks to investigate their mechanisms of action.RNA sequencing of cardiac tissue was performed to investigate the mechanism of anti-heart failure action of ZWD, and potential binding proteins of Galloypaeoniflorin (GAL), an effective monomer component of ZWD, were verified by molecular docking, DARTS, CETSA and SPR. The results showed that ZWD conferred a protective effect against Ang II-induced cardiac dysfunction in mice by inhibiting cardiac hypertrophy and inflammation. RNA sequencing revealed that this cardioprotective effect was associated with the MAPKs/STAT2-NLRC5 signaling pathway. GAL alleviated the inflammatory response in mouse heart tissues and in vitro cultured cardiomyocytes by inhibiting the Ang II-stimulated MAPKs/STAT2-NLRC5 signaling pathway. The data suggest that deficiency of MAPKs or STAT2 in cardiomyocytes abolished the anti-inflammatory effects of GAL. Molecular docking, DARTS, CETSA and SPR techniques confirmed the binding of GAL and STAT2. Our study suggests that ZWD protects the heart from damage caused by Ang II stimulation by targeting STAT2 through inhibiting the inflammatory response driven by the MAPK signaling pathway, indicating its promising application in the treatment of hypertensive heart failure.