Shenfu Administration Improves Cardiac Fibrosis in Rats With Myocardial Ischemia-Reperfusion Through Adenosine A_2a Receptor Activation

Abstract

Objective Shenfu injection (SFI) is commonly used for cardiac dysfunction in China. Adenosine receptors have been reported to exert anti-fibrosis effects. The intent of this study was to evaluate that SFI attenuates cardiac fibrosis through activating of adenosine A2a receptor (A2aR) in rats with myocardial ischemia-reperfusion (MI/R). Methods Sprague Dawley male rats were randomly divided into five groups, nine rats in each group. Injections in all rat groups were carried out prior to reperfusion, and in the sham and MI/R groups, only vehicle was injected. Injections in the remaining group were as follows: 5 mL/kg in the SFI group; 15 mg/kg nicorandil in the A2R agonist group; and 5 mL/kg SFI plus 5 mg/kg MSX-3 in the SFI + A2aR antagonist group. Changes in cyclic adenosine monophosphate (cAMP) and the development of myocardial infarction and cardiac fibrosis were documented among the groups. Additionally, the levels of A2aR, collagen Ⅰ, collagen Ⅲ, fibronectin, and matrix metalloproteinase-9 (MMP-9) were measured. Results Following injection with SFI or nicorandil, the cAMP concentration, infarct area, and cardiac fibrosis induced by MI/R injury were significantly decreased ( p < 0.05). Additionally, the levels of collagen Ⅰ, collagen Ⅲ, fibronectin, and MMP-9 were clearly suppressed by SFI or nicorandil when compared with the MI/R group ( p<0.01). However, the protective effects of SFI were counteracted by MSX-3. A negative correlation between A2aR and collagen I and collagen III was found ( p = 0.00). Conclusion SFI activated the A2aR to reduce myocardial fibrosis caused by MI/R injury, which provided an underlying mechanism of action of SFI.

Shenfu injection: a review of pharmacological effects on cardiovascular diseases

“…Inflammatory cells can also stimulate repair pathways, with increasing the content of extracellular matrix in the myocardium, including matrix metalloproteinase-9 (MMP-9) and collagen ( Valiente-Alandi et al, 2018 ). SFI has anti-inflammatory effect, which can reduce the content of inflammatory factors such as tumor necrosis factor-α (TNF-α), interleukin-1𝛽 (IL-1𝛽) and interleukin-6 (IL-6) in serum of rats, and also reduce the expression of fibronectin, collagen I, collagen III and MMP-9 protein ( Ni et al, 2017 ; Guo et al, 2022 ).…”

“…(IL-1?) and interleukin-6 (IL-6) in serum of rats, and also reduce the expression of fibronectin, collagen I, collagen III and MMP-9 protein (Ni et al, 2017;Guo et al, 2022).…”

Off-Target Effects of P2Y12 Receptor Inhibitors: Focus on Early Myocardial Fibrosis Modulation

“…Additionally, a study conducted in China in 2022 shed light on the beneficial effects of Shenfu injection (SFI), a commonly employed treatment for cardiac dysfunction in China. The study illustrated that SFI attenuated cardiac fibrosis through the activation of adenosine A2A receptors (A2ARs) in a rat model of myocardial ischemia-reperfusion (MI/R) [48].…”

Biglycan Involvement in Heart Fibrosis: Modulation of Adenosine 2A Receptor Improves Damage in Immortalized Cardiac Fibroblasts

“…The protective role of BGN downregulation is probably due to its involvement as a structural molecule in the assembly of collagen, as well as its action as a signaling molecule in stimulating different cell functions [ 20 , 24 , 25 ]. In fact, previous studies already demonstrated that the adenosine A 2A receptor may contribute to the development of fibrotic damage mainly through the stimulation of collagen production and deposition [ 28 , 29 ], and its modulation might be useful to manage cardiac fibrosis by limiting fibrotic scar deposition in tissue [ 30 ] and also in the heart [ 31 , 32 ].…”