4-Hydroxychalcone attenuates AngII-induced cardiac remodeling and dysfunction via regulating PI3K/AKT pathway

Cardiac remodeling encompasses structural alterations such as hypertrophy, fibrosis, and dilatation, alongside numerous cellular and molecular functional aberrations, constituting a pivotal process in the advancement of heart failure (HF). 4-Hydroxychalcone (4-HCH) is a class of naturally occurring compounds with variable phenolic structures, and has demonstrated the preventive efficacy in hyperaldosteronism, inflammation and renal injury. However, the role of 4-HCH in the regulation of cardiac remodeling remains uncertain. A cardiac remodeling model was established in male C57BL/6 J mice via subcutaneous Ang II (1000 or 300 ng/kg/min) for 2 weeks. Mice were treated with 4-HCH (20 or 40 mg/kg/day) or vehicle control. Systolic blood pressure (SBP) was measured using a tail-cuff method, and echocardiography assessed cardiac function. Histopathological staining evaluated cardiomyocyte hypertrophy, fibrosis, inflammation, and superoxide production. Network pharmacology analysis identified potential core targets and pathways mediating the effects of 4-HCH. Expression of inflammatory cytokines and proteins related to hypertrophy, fibrosis, inflammation, and oxidative stress was assessed by quantitative real-time PCR (qPCR) and Western blotting. Our results indicated that 4-HCH significantly ameliorated Ang II-induced hypertension, cardiomyocyte hypertrophy, fibroblast activation, fibrosis, inflammation, superoxide production, and cardiac function. Network pharmacology analysis identified the PI3K-AKT pathway as a crucial mechanism underlying the effects of 4-HCH, with experimental verification demonstrating that it inhibits cardiac remodeling by downregulating this pathway and its downstream effectors, including mTOR/ERK, TGF-β/Smad2/3, NF-κB, and NOX1 independent of its blood pressure-lowering effects. These results reveal for the first time that 4-HCH alleviates cardiac remodeling, emphasizing its potential as a therapeutic agent for HF.