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. 2024 Feb 24;19(1):30.
doi: 10.1186/s13020-024-00902-4.

Optimized New Shengmai Powder modulation of cAMP/Rap1A signaling pathway attenuates myocardial fibrosis in heart failure

Zeyu Zhang #  1   2 , Zhe Xu #  2 , Shuai Wang  1 , Zhuangzhuang Jia  1 , Zhou Zhou  1   2 , Ci Wang  1   2 , Shanshan Lin  1   2 , Yiting Feng  1   2 , Xianliang Wang  3 , Jingyuan Mao  4
Affiliations

Optimized New Shengmai Powder modulation of cAMP/Rap1A signaling pathway attenuates myocardial fibrosis in heart failure

Zeyu Zhang et al. Chin Med. .

Abstract

Background: Optimized New Shengmai Powder (ONSMP) is a traditional Chinese medicine formula with significant anti-heart failure and myocardial fibrosis effects, but the specific molecular biological mechanisms are not fully understood.

Methods: In this study, we first used network pharmacology to analyze the ONSMP's active ingredients, core signaling pathways, and core targets. Second, calculate the affinity and binding modes of the ONSMP components to the core targets using molecular docking. Finally, the heart failure rat model was established by ligating the left anterior descending branch of the coronary artery and assessing the effect of ONSMP on myocardial fibrosis in heart failure using echocardiography, cardiac organ coefficients, heart failure markers, and pathological sections after 4 weeks of drug intervention. The cAMP level in rat myocardium was determined using Elisa, the α-SMA and FSP-1 positive expression determined by immunohistochemistry, and the protein and mRNA levels of the cAMP/Rap1A signaling pathway were detected by Western Blotting and quantitative real-time PCR, respectively.

Results: The result shows that the possible mechanism of ONSMP in reducing myocardial fibrosis also includes the use of 12 active ingredients such as baicalin, vitamin D, resveratrol, tanshinone IIA, emodin, 15,16-dihydrotanshinone-i to regulate β1-AR, AC6, EPAC1, Rap1 A, STAT3, and CCND1 on the cAMP/Rap1A signaling pathway, thereby inhibiting the proliferation of cardiac fibroblasts and reduce the excessive secretion of collagen, effectively improve cardiac function and ventricular remodeling in heart failure rats.

Conclusion: This research shows that ONSMP can inhibit myocardial fibrosis and delay heart failure through the cAMP/Rap1A signaling pathway.

Keywords: Heart failure; Myocardial fibrosis; Optimized New Shengmai Powder; Traditional Chinese medicine; cAMP/Rap1A signaling pathway.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Fig. 1
Fig. 1
Network pharmacology analysis of ONSMP on myocardial fibrosis in heart failure. A Access to drug-disease intersection targets. B Bar graph of GO functional enrichment analysis of intersection targets. C Bubble diagram of KEGG signaling pathway enrichment analysis of intersection targets. D Topological analysis of the cAMP/Rap1A signaling pathway with enriched targets. E Acquisition of core targets of cAMP and Rap1A signaling pathways. The orange rectangle is the target that meets the screening conditions, the blue-green rectangle is the target that does not meet the screening conditions, and the orange oval is the core target. F Topological analysis of ONSMP active ingredients with core targets of cAMP and Rap1A signaling pathways
Fig. 2
Fig. 2
Action modes of active compounds with core targets. A Baicalin & β1-AR. B Vitamin D & AC6. C Resveratrol & EPAC1. D Tanshinone IIA & RAP1A. E Emodin & STAT3. F 15,16-dihydrotanshinone-i & CCND1
Fig. 3
Fig. 3
Echocardiographic and cardiac organ coefficient of rats in each group. A Typical echocardiograms. B-O Statistical plots of LVEF, LVFS, IVSd, IVSs, LVIDd, LVIDs, LVPWd, LVPWs, E/A, HWI, LVWI, HW/TL, LVW/TL, and SI. Data are presented as mean ± SD, n = 6. ##P < 0.01 vs the sham; *P < 0.05, **P < 0.01 vs the model; &P < 0.05, &&P < 0.01 vs the ONSMP-L
Fig. 4
Fig. 4
Serum heart failure markers and myocardial cAMP levels of rats in each group. A–H Statistical plots of ANP, BNP, NT-ProBNP, PICP, MMP-2, MMP-9, TIMP-1, and cAMP. Data are presented as mean ± SD, n = 3. ##P < 0.01 vs the sham; *P < 0.05, **P < 0.01 vs the model; &P < 0.05 vs the ONSMP-L
Fig. 5
Fig. 5
Myocardial histopathologic sections and immunohistochemical results of rats in each group. A Representative rat myocardial pathological sections (HE, Sirius red, and Masson) and immunohistochemical sections (α-SMA and FSP-1) (× 400). B–E Statistical plots of CVF of Sirius red, CVF of Masson, α-SMA positive expression, and FSP-1 positive expression. Data are presented as mean ± SD n = 3. ##P < 0.01 vs the sham; **P < 0.01 vs the model
Fig. 6
Fig. 6
Effect of ONSMP on cAMP/Rap1A signaling pathway and myocardial fibrosis effector proteins. A, B Representative Western blot strips of cAMP/Rap1A signaling pathway and myocardial fibrosis effector proteins in myocardium with GAPDH as an internal reference. C–L Statistical plots of β1-AR, AC6, Epac1, Rap1A-GTP, p-STAT3, CCND1, α-SMA, FSP-1, COL I, and COL III. Data are presented as mean ± SD, n = 3. ##P < 0.01 vs the sham; *P < 0.05, **P < 0.01 vs the model; &&P < 0.01 vs the ONSMP-L; ※P < 0.05, ※※P < 0.01 vs the ONSMP-H
Fig. 7
Fig. 7
Effect of ONSMP on cAMP/Rap1A signaling pathway and myocardial fibrosis effector mRNA mRNA. A–J Statistical plots of β1-AR, AC6, Epac1, Rap1A, STAT3, CCND1, α-SMA, FSP-1, COL I, and COL III mRNA in myocardium. Data are presented as mean ± SD, n = 3. ##P < 0.01 vs the sham; *P < 0.05, **P < 0.01 vs the model; &&P < 0.01 vs the ONSMP-L
Fig. 8
Fig. 8
Relationship of the cAMP/Rap1A signaling pathway to myocardial fibrosis in heart failure
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