Danshen and Zhizi Compatibility Alleviates Heart Injury and Cardiac Ferroptosis in Myocardial Infarction in Rats by Cyclic Adenosine Monophosphate/Protein Kinase A Signaling
DOI:
https://doi.org/10.59958/hsf.7149Keywords:
Danshen and Zhizi Compatibility, cAMP-PKA, ferroptosis, myocardial infarctionAbstract
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.
References
Xu T, Ding W, Tariq MA, Wang Y, Wan Q, Li M, et al. Molecular mechanism and therapy application of necrosis during myocardial injury. Journal of Cellular and Molecular Medicine. 2018; 22: 2547–2557.
Talman V, Ruskoaho H. Cardiac fibrosis in myocardial infarction-from repair and remodeling to regeneration. Cell and Tissue Research. 2016; 365: 563–581.
Colombe AS, Pidoux G. Cardiac cAMP-PKA Signaling Compartmentalization in Myocardial Infarction. Cells. 2021; 10: 922.
Nishida H, Sato T, Miyazaki M, Nakaya H. Infarct size limitation by adrenomedullin: protein kinase A but not PI3-kinase is linked to mitochondrial KCa channels. Cardiovascular Research. 2008; 77: 398–405.
Xia Y, He F, Moukeila Yacouba MB, Zhou H, Li J, Xiong Y, et al. Adenosine A2a Receptor Regulates Autophagy Flux and Apoptosis to Alleviate Ischemia-Reperfusion Injury via the cAMP/PKA Signaling Pathway. Frontiers in Cardiovascular Medicine. 2022; 9: 755619.
Bryson TD, Gu X, Khalil RM, Khan S, Zhu L, Xu J, et al. Overexpression of prostaglandin E2 EP4 receptor improves cardiac function after myocardial infarction. Journal of Molecular and Cellular Cardiology. 2018; 118: 1–12.
Karam S, Margaria JP, Bourcier A, Mika D, Varin A, Bedioune I, et al. Cardiac Overexpression of PDE4B Blunts β-Adrenergic Response and Maladaptive Remodeling in Heart Failure. Circulation. 2020; 142: 161–174.
Ye Y, Keyes KT, Zhang C, Perez-Polo JR, Lin Y, Birnbaum Y. The myocardial infarct size-limiting effect of sitagliptin is PKA-dependent, whereas the protective effect of pioglitazone is partially dependent on PKA. American Journal of Physiology. Heart and Circulatory Physiology. 2010; 298: H1454–H1465.
Li XD, Yang YJ, Geng YJ, Zhao JL, Zhang HT, Cheng YT, et al. Phosphorylation of endothelial NOS contributes to simvastatin protection against myocardial no-reflow and infarction in reperfused swine hearts: partially via the PKA signaling pathway. Acta Pharmacologica Sinica. 2012; 33: 879–887.
Qu C, Xu DQ, Yue SJ, Shen LF, Zhou GS, Chen YY, et al. Pharmacodynamics and pharmacokinetics of Danshen in isoproterenol-induced acute myocardial ischemic injury combined with Honghua. Journal of Ethnopharmacology. 2020; 247: 112284.
Li ZM, Xu SW, Liu PQ. Salvia miltiorrhizaBurge (Danshen): a golden herbal medicine in cardiovascular therapeutics. Acta Pharmacologica Sinica. 2018; 39: 802–824.
Wang X, Guo D, Li W, Zhang Q, Jiang Y, Wang Q, et al. Danshen (Salvia miltiorrhiza) restricts MD2/TLR4-MyD88 complex formation and signalling in acute myocardial infarction-induced heart failure. Journal of Cellular and Molecular Medicine. 2020; 24: 10677–10692.
Li Y, Zhang K, Liu J, Liu S, Nie C, Yan Y, et al. Geniposide suppresses thermogenesis via regulating PKA catalytic subunit in adipocytes. Toxicology. 2021; 464: 153014.
Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012; 149: 1060–1072.
Stockwell BR. Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications. Cell. 2022; 185: 2401–2421.
Wang XD, Kang S. Ferroptosis in myocardial infarction: not a marker but a maker. Open Biology. 2021; 11: 200367.
Han X, Zhang J, Liu J, Wang H, Du F, Zeng X, et al. Targeting ferroptosis: a novel insight against myocardial infarction and ischemia-reperfusion injuries. Apoptosis: an International Journal on Programmed Cell Death. 2023; 28: 108–123.
Wu YT, Zhang GY, Hua Y, Fan HJ, Han X, Xu HL, et al. Ferrostatin-1 suppresses cardiomyocyte ferroptosis after myocardial infarction by activating Nrf2 signaling. The Journal of Pharmacy and Pharmacology. 2023; 75: 1467–1477.
Zhang X, Hu C, Ma ZG, Hu M, Yuan XP, Yuan YP, et al. Tisp40 prevents cardiac ischemia/reperfusion injury through the hexosamine biosynthetic pathway in male mice. Nature Communications. 2023; 14: 3383.
Jiang Y, Qiao Y, He D, Tian A, Li Z. Adaptor protein HIP-55-mediated signalosome protects against ferroptosis in myocardial infarction. Cell Death and Differentiation. 2023; 30: 825–838.
Shen Y, Wang X, Shen X, Wang Y, Wang S, Zhang Y, et al. Geniposide Possesses the Protective Effect on Myocardial Injury by Inhibiting Oxidative Stress and Ferroptosis via Activation of the Grsf1/GPx4 Axis. Frontiers in Pharmacology. 2022; 13: 879870.
Shen Y, Shen X, Wang S, Zhang Y, Wang Y, Ding Y, et al. Protective effects of Salvianolic acid B on rat ferroptosis in myocardial infarction through upregulating the Nrf2 signaling pathway. International Immunopharmacology. 2022; 112: 109257.
Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. Journal of Computational Chemistry. 2010; 31: 455–461.
Liu C, Du L, Zhang S, Wang H, Kong L, Du G. Network pharmacology and experimental study of phenolic acids in salvia miltiorrhiza bung in preventing ischemic stroke. Frontiers in Pharmacology. 2023; 14: 1108518.
Tao W, Xu X, Wang X, Li B, Wang Y, Li Y, et al. Network pharmacology-based prediction of the active ingredients and potential targets of Chinese herbal Radix Curcumae formula for application to cardiovascular disease. Journal of Ethnopharmacology. 2013; 145: 1–10.
Xu X, Qiu J, Li X, Chen J, Li Y, Huang X, et al. Perilipin5 protects against non-alcoholic steatohepatitis by increasing 11-Dodecenoic acid and inhibiting the occurrence of ferroptosis. Nutrition & Metabolism. 2023; 20: 29.
Zheng P, Xie Z, Yuan Y, Sui W, Wang C, Gao X, et al. Plin5 alleviates myocardial ischaemia/reperfusion injury by reducing oxidative stress through inhibiting the lipolysis of lipid droplets. Scientific Reports. 2017; 7: 42574.
Zhang X, Xu W, Xu R, Wang Z, Zhang X, Wang P, et al. Plin5 Bidirectionally Regulates Lipid Metabolism in Oxidative Tissues. Oxidative Medicine and Cellular Longevity. 2022; 2022: 4594956.
Liu L, Yang S, Wang H. α-Lipoic acid alleviates ferroptosis in the MPP+ -induced PC12 cells via activating the PI3K/Akt/Nrf2 pathway. Cell Biology International. 2021; 45: 422–431.
Cadenas S. ROS and redox signaling in myocardial ischemia-reperfusion injury and cardioprotection. Free Radical Biology & Medicine. 2018; 117: 76–89.
Wu X, Li Y, Zhang S, Zhou X. Ferroptosis as a novel therapeutic target for cardiovascular disease. Theranostics. 2021; 11: 3052–3059.
Huang WT, Li CJ, Wu PJ, Chang YS, Lee TL, Weng CF. Expression and in vitro regulation of pituitary adenylate cyclase-activating polypeptide (pacap38) and its type I receptor (pac1-r) in the gonads of tilapia (Oreochromis mossambicus). Reproduction (Cambridge, England). 2009; 137: 449–467.
Huang CK, Dai D, Xie H, Zhu Z, Hu J, Su M, et al. Lgr4 Governs a Pro-Inflammatory Program in Macrophages to Antagonize Post-Infarction Cardiac Repair. Circulation Research. 2020; 127: 953–973.
Lai P, Nikolaev VO, De Jong KA. Understanding the Role of SERCA2a Microdomain Remodeling in Heart Failure Induced by Obesity and Type 2 Diabetes. Journal of Cardiovascular Development and Disease. 2022; 9: 163.
