Shunxin decoction (顺心组方) improves diastolic function in rats with heart failure with preserved ejection fraction induced by abdominal aorta constriction through cyclic guanosine monophosphate-dependent protein kinase Signaling Pathway

doi:10.19852/j.cnki.jtcm.20220519.003

Abstract

Abstract:

OBJECTIVE: To determine whether Shunxin decoction (顺心组方) improves diastolic function in rats with heart failure with preserved ejection fraction (HFpEF) by regulating the cyclic guanosine monophosphate-dependent protein kinase (cGMP-PKG) signaling pathway.

METHODS: Except for control group 8 and sham surgery group 8, the remaining 32 male Sprague-Dawlay rats were developed into HFpEF rat models using the abdominal aorta constriction method. These rats in the HFpEF model were randomly divided into the model group, the Shunxin high-dose group, the Shunxin low-dose group, and the Qiliqiangxin capsule group. The three groups received high-dose Shunxin decoction, low-dose Shunxin decoction, and Qiliqiangxin capsule by gavage, respectively, for 14 d. After the intervention, the diastolic function of each rat was evaluated by testing E/A, heart index, hematoxylin-eosin staining, Masson, myocardial ultrastructure, and N-terminal pro-brain natriuretic peptide (NT-proBNP). The Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine (BATMAN-TCM) software was used to predict targets for which Shunxin decoction acts on the cGMP-PKG pathway. Natriuretic peptide receptor A (NPRA) and guanylate cyclase (GC) were detected by immunohistochemistry, and eNOS, phosphodiesterase 5A (PDE5A), and cGMP-dependent protein kinase 1(PKG I) were determined by Western blotting.

RESULTS: Compared to the model group, the thickness of the interventricular septum at the end of diastole (IVSd) and the thickness of the posterior wall at the end of diastole (PWd) of the Shunxin decoction high-dose group, Shunxin decoction low-dose group, and Qiliqiangxin capsule group were all significantly reduced (P < 0.01). Furthermore, Shunxin decoction high-dose group E/A value was decreased (P < 0.01). Compared to the model group, the expression of NPRA and GC increased in the Shunxin decoction low-dose group and the Qiliqiangxin capsule group (P < 0.01). Compared to the model group, the expressions of eNOS and PKG I increased (P < 0.05) in the Shunxin decoction high-dose group. The expression of PDE5A expression decreased in the myocardium of the Shunxin decoction high-dose group, Shunxin decoction low-dose group, and Qiliqiangxin capsule group compared to the model group (P < 0.01).

CONCLUSIONS: Shunxin decoction can improve diastolic function in rats with HFpEF. It increases the expression of NPRA, GC, and eNOS in the myocardial cell cGMP-PKG signaling pathway, upregulates cGMP expression, decreases PDE5A expression to reduce the cGMP degradation. Thus, the cGMP continually stimulates PKG I, reversing myocardial hypertrophy and improving myocardial compliance in HFpEF rats.

Key words: heart failure, preserved ejection fraction, diastole, cyclic GMP-dependent protein kinases, signal transduction, Shunxin decoction

ZHANG Jiaying, WEI Xiangxiang, LI Xuefeng, YUAN Yang, DOU Yinghuan, SHI Yanbin, XIE Ping, ZHOU Mengru, ZHAO Junnan, LI Miao, ZHANG Shuwen, ZHU Rui, TIAN Ying, TAN Hao, TIAN Feifei. Shunxin decoction (顺心组方) improves diastolic function in rats with heart failure with preserved ejection fraction induced by abdominal aorta constriction through cyclic guanosine monophosphate-dependent protein kinase Signaling Pathway[J]. Journal of Traditional Chinese Medicine, 2022, 42(5): 764-772.

Figures/Tables 4

Figure 1 Cardiac function in rats in each group after three months of surgery A: echocardiography, include A1-C2. A1, A2: control group; B1, B2: sham group; C1, C2: model group. B: IVSd comparison; C: PWd comparison; D: E/A comparison. aP < 0.01, vs control group. IVSd: interventricular septal thickness at end-diastole; PWd: the posterior wall thickness at end-diastole; E value: the peak blood flow in the early mitral diastolic period; A value: late mitral diastolic period; E/A= E value/ A value.

Figure 2 Cardiac function in rats in each group after drug intervention A: echocardiography, include A1-F2. A1, A2: control group; B1, B2: sham group; C1, C2: model group; D1, D2: Shunxin high-dose group; E1, E2: Shunxin low-dose group; F1, F2: Qiliqiangxin group. B: IVSd comparison; C: PWd comparison; D: E/A comparison. Control, sham surgery and model groups: treated only with normal saline; Shunxin decoction high-dose group: treated with Shunxin decoction 42.81 g/kg, Shunxin decoction low-dose group: treated with Shunxin decoction 14.27 g/kg, and Qiliqiangxin capsule intervention group: treated with Qiliqiangxin capsule 0.375 g/kg, every group by intragastric gavage for 14 d. aP < 0.01, vs control group; bP < 0.01, vs model group. IVSd: interventricular septal thickness at end-diastole; PWd: the posterior wall thickness at end-diastole; E value: the peak blood flow in the early mitral diastolic period; A value: late mitral diastolic period; E/A= E value/ A value.

Figure 3 Morphological observation of rat myocardium in each group A: hematoxylin-eosin staining (magnification ×400); B: Cardiac index, vs control, aP < 0.05; C: Masson staining (magnification ×400); D: Cardiac CVF, vs control, aP < 0.05. A1, A2: control group; B1, B2: sham group; C1, C2: model group; D1, D2: Shunxin high-dose group; E1, E2: Shunxin low-dose group; F1, F2: Qiliqiangxin group. E: a: ultrastructure of rat myocardium (×10 000); b: ultrastructure of myocardial mitochondria (×20 000); c: ultrastructure of myocardial myofibrils (×20 000). CVF: collagen volume fraction. Control, sham surgery and model groups: treated only with normal saline; Shunxin decoction high-dose group: treated with Shunxin decoction 42.81 g/kg, Shunxin decoction low-dose group: treated with Shunxin decoction 14.27 g/kg, and Qiliqiangxin capsule intervention group: treated with Qiliqiangxin capsule 0.375 g/kg, every group by intragastric gavage for 14 d.

Figure 4 Expression of major target moleculars of cGMP-PKG pathway in each group A: immunohistochemical method used to detect the expression of myocardial NPRA in rats (magnification × 400); B: comparison of myocardial NPRA in rats among groups, vs control, aP < 0.01; vs model, bP < 0.01; C: immunohistochemical method used to detect the expression of myocardial GC in rats, vs control, aP < 0.01; vs model, bP < 0.01; D: comparisons of myocardial GC in rats among groups; E: WB detection of myocardial eNOS; PDE5A; and PKG I expressions in rats; F: eNOS; G: PDE5A, vs control, aP < 0.01; vs model, bP < 0.01; H: PKGⅠ, vs control, aP < 0.01; vs model, bP < 0.05. A1, A2: control group; B1, B2: sham group; C1, C2: model group; D1, D2: Shunxin high-dose group; E1, E2: Shunxin low-dose group; F1, F2: Qiliqiangxin group. Control, sham surgery and model groups: treated only with normal saline; Shunxin decoction high-dose group: treated with Shunxin decoction 42.81 g/kg, Shunxin decoction low-dose group: treated with Shunxin decoction 14.27 g/kg, and Qiliqiangxin capsule intervention group: treated with Qiliqiangxin capsule 0.375 g/kg, every group by intragastric gavage for 14 d. NPRA: natriuretic peptide receptor A; GC: guanylate cyclase; eNOS: endothelial nitric oxide synthase; PDE5A: phosphodiesterase 5A; PKG I: cyclic guanosine monophosphate-dependent protein kinase 1.

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