Baoyuan decoction (BYD) attenuates cardiac hypertrophy through ANKRD1-ERK/GATA4 pathway in heart failure after acute myocardial infarction

Hui Meng, Zhiyong Du, Wenji Lu, Qixin Wang, Xiaoqian Sun, Yong Jiang, Yong Wang, Chun Li, Pengfei Tu
Background: The pathological cardiac functions of ankyrin repeat domain 1 (ANKRD1) in left ventricle can directly aggravate cardiac hypertrophy (CH) and fibrosis through the activation of extracellular signal-regulated kinase (ERK)/ transcription factor GATA binding protein 4 (GATA4) pathway, and subsequently contribute to heart failure (HF). Baoyuan Decoction (BYD), which is a famous classic Chinese medicinal formulation, has shown impressive cardioprotective effects clinically and experimentally. However, the knowledge is still limited in its underlying mechanisms against HF. Purpose: To explore whether BYD plays a protective role against HF by attenuating CH via the ANKRD1-ERK/ GATA4 pathway. Methods: In vivo, HF rat models were prepared using left anterior descending coronary artery (LADCA) ligation. Rats in the BYD group were administered a dosage of 2.57 g/kg of BYD for 28 days, while in the positive control group rats were given 4.67 mg/kg of Fosinopril. In vitro, a hypertrophic model was constructed by stimulating H9C2 cells with 1 uM Ang II. An ANKRD1-overexpressing cell model was established through transient trans- fection of ANKRD1 plasmid into H9C2 cells. Subsequently, BYD intervention was performed on the cell models to further elucidate its effects and underlying mechanism. Results: In vivo results showed that BYD significantly improved cardiac function and inhibited pathological hy- pertrophy and fibrosis in a rat model of HF post-acute myocardial infarction (AMI). Noticeably, label-free pro- teomic analysis demonstrated that BYD could reverse the CH-related biological turbulences, mainly through ANKRD1-ERK/GATA4 pathway. Further in vitro results validated that the hypertrophy was attenuated by BYD through suppression of AT1R, ANKRD1, Calpain1, p-ERK1/2 and p-GATA4. The results of in vitro model indicated that BYD could reverse the outcome of transfected over-expression of ANKRD1, including down- regulated expressions of ANKRD1, p-ERK1/2 and p-GATA4. Conclusion: BYD ameliorates CH and improves HF through the ANKRD1-ERK/GATA4 pathway, providing a novel therapeutic option for the treatment of HF.

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