Danshen and Zhizi Compatibility Alleviates Heart Injury and Cardiac Ferroptosis in Myocardial Infarction in Rats by Cyclic Adenosine Monophosphate/Protein Kinase A Signaling

Objective: To investigate the effect and mechanism of the Danshen and Zhizi Compatibility (DZ) on alleviating heart injury and cardiac ferroptosis in rats with myocardial infarction. Methods: A rat model of myocardial infarction was established by ligation of the left anterior descending artery. The rats were equally and randomly divided into 5 groups. The sham group underwent open-chest surgery without arterial ligation, while the other 4 groups underwent surgery, including 3 groups treated with low dose (4 g/kg/d), high dose (8 g/kg/d) DZ and high dose (8 g/kg/d) DZ supplemented with H-89 (0.5 mg/kg/d) respectively. The sham and myocardial infarction group received the same volume of saline. 14 days after surgery, the serum and heart tissues were harvested to detect cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) activity, heart injury and the level of ferroptosis. Results: G-protein coupled receptors (GPCRs) have a high binding affinity with the main components of DZ, which indicated that DZ probably contributed to ameliorating cardiac injury by activating downstream cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling. Treatment with the high dose of DZ significantly increased cAMP concentration in the serum, PKA activity in the heart tissue and upregulated perilipin (PLIN)5 expression. DZ significantly attenuated heart injury, whereas H-89 reversed the protective effects of DZ. In addition, DZ administration inhibited ferroptosis as evidenced by reduced malondialdehyde (MDA), and 4-hydroxynonenal (4-HNE) levels. In addition, DZ increased glutathione (GSH) levels and Glutathione peroxidase (GPX)4 protein expression in heart tissue, whereas H-89 abrogated the regulatory effect of DZ. Conclusion: Our results demonstrated that DZ alleviated heart injury and cardiac ferroptosis in myocardial infarction through the cAMP-PKA signalling pathway.