Objective:

2

To investigate the protective mechanisms of Chinese medicine Shexiang Tongxin Dropping Pills (STDP) on heart failure (HF).

Methods:

2

Isoproterenol (ISO)-induced HF rat model and angiotensin Ⅱ (Ang Ⅱ)-induced neonatal rat cardiac fibroblast (CFs) model were used in the present study. HF rats were treated with and without STDP (3 g/kg). RNA-seq was performed to identify differentially expressed genes (DEGs). Cardiac function was evaluated by echocardiography. Hematoxylin and eosin and Masson's stainings were taken to assess cardiac fibrosis. The levels of collagen Ⅰ (Col Ⅰ) and collagen Ⅲ (Col Ⅲ) were detected by immunohistochemical staining. CCK8 kit and transwell assay were implemented to test the CFs' proliferative and migratory activity

respectively. The protein expressions of α-smooth muscle actin (α-SMA)

matrix metalloproteinase-2 (MMP-2)

MMP-9

Col Ⅰ

and Col Ⅲ were detected by Western blotting.

Results:

2

The results of RNA-seq analysis showed that STDP exerted its pharmacological effects on HF via multiple signaling pathways

such as the extracellular matrix (ECM)-receptor interaction

cell cycle

and B cell receptor interaction. Results from

in vivo

experiments demonstrated that STDP treatment reversed declines in cardiac function

inhibiting myocardial fibrosis

and reversing increases in Col Ⅰ and Col Ⅲ expression levels in the hearts of HF rats. Moreover

STDP (6

9 mg/mL) inhibited the proliferation and migration of CFs exposed to Ang Ⅱ

in vitro

(

P

<

0.05). The activation of collagen synthesis and myofibroblast generation were markedly suppressed by STDP

also the synthesis of MMP-2 and MMP-9

as well as ECM components Col Ⅰ

Col Ⅲ

and α-SMA were decreased in Ang Ⅱ-induced neonatal rats' CFs.

Conclusions:

2

STDP had anti-fibrotic effects in HF

which might be caused by the modulation of ECM-receptor interaction pathways. Through the management of cardiac fibrosis

STDP may be a compelling candidate for improving prognosis of HF.