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. 2020 Dec;58(1):417-426.
doi: 10.1080/13880209.2020.1761403.

Qiliqiangxin improves cardiac function and attenuates cardiac remodelling in doxorubicin-induced heart failure rats

Xutao Sun  1 , Guozhen Chen  2 , Ying Xie  1 , Deyou Jiang  1 , Jieru Han  1 , Fei Chen  1 , Yunjia Song  1   3
Affiliations

Qiliqiangxin improves cardiac function and attenuates cardiac remodelling in doxorubicin-induced heart failure rats

Xutao Sun et al. Pharm Biol. 2020 Dec.

Abstract

Context: Therapeutic doxorubicin administration is restricted as this anticancer drug may be cardiotoxic. The traditional Chinese medicine qiliqiangxin has been approved for clinical treatment of chronic heart failure.Objective: To explore the protective effects and molecular mechanisms of qiliqiangxin on doxorubicin-induced congestive heart failure (CHF) in rats.Materials and methods: A CHF rat model was established via intraperitoneal DOX injections (2.5 mg/kg/week) for 6 weeks. The rats were randomly assigned to control, CHF, CHF + QL (1.0 g/kg/d), or captopril (3.8 mg/kg/d) treatment groups (n = 10) for 4 weeks. MicroRNA sequencing elucidated the molecular mechanisms of qiliqiangxin on doxorubicin-induced CHF in rats.Results: Unlike in the CHF group, QL significantly reduced Bax:Bcl-2 (2.05 ± 0.23 vs. 0.94 ± 0.09, p < 0.05) and the levels of collagen I (0.19 ± 0.02 vs. 0.15 ± 0.01, p < 0.05), collagen III (0.19 ± 0.02 vs. 0.14 ± 0.02, p < 0.05), TGF-β1 (5.28 ± 0.89 vs. 2.47 ± 0.51, p < 0.05), Smad3 (1.23 ± 0.12 vs. 0.78 ± 0.09, p < 0.05), MMP-2 (0.89 ± 0.01 vs. 0.53 ± 0.05, p < 0.05), and TIMP-2 (0.24 ± 0.03 vs. 0.44 ± 0.03, p < 0.05). QL also upregulated TGF-β3 (0.65 ± 0.06 vs. 0.96 ± 0.10, p < 0.05) and Smad7 (0.09 ± 0.01 vs. 0.19 ± 0.023, p < 0.05). Moreover, Smad3 was a target of miR-345-3p.Discussion and Conclusions: The beneficial effects of QL on DOX-induced CHF in rats are mediated by reduction in myocardial fibrosis, promotion of TGF-β3/Smad7, and inhibition of TGF-β1/Smad3. QL may also modulate specific miRNAs. These results provide evidence that QL might be an effective treatment for DOX-induced CHF.

Keywords: Chronic heart failure; TGF-β1/Smad3; TGF-β3/Smad7; miRNAs.

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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

Figure 1.
Figure 1.
QL restored cardiac function in DOX-induced CHF. (A) M-mode echocardiographic images of each treatment group. (B) Cardiac function was determined by EF, FS, LVIDd and LVIDs and compared among the different groups by echocardiography. (C) Comparison of the hemodynamic parameters LVSP, LVEDP, +dp/dtmax and − dp/dtmax among different groups after QL treatment. *p < 0.05, **p < 0.01 vs. control group. #p < 0.05, ##p < 0.01 vs. CHF group.
Figure 2.
Figure 2.
QL improved myocardium ultrastructure and reduced fibrosis. (A) TEM images of left ventricles of rats. (B, C) IHC disclosed that QL markedly downregulated collagens I and III. (D) Collagens I and III positive integral optical density. *p < 0.05, **p < 0.01 vs. control group. #p < 0.05, ##p < 0.01 vs. CHF group.
Figure 3.
Figure 3.
QL suppressed apoptosis and inflammation in DOX-induced CHF rats. (A, B) IHC images showing that QL downregulated Bax and upregulated Bcl-2. (C, D) ICH images showing that QL treatment downregulated MMP-2 and TIMP-2. (E) Analysis of Bax and Bcl-2 positive integral optical density. (F) ELISA demonstrated that QL substantially downregulated MMP-2 and TIMP-2. *p < 0.05, **p < 0.01 vs. control group. #p < 0.05, ##p < 0.01 vs. CHF group.
Figure 4.
Figure 4.
QL promoted the cardiac TGF-β3/signalling pathway Smad7 and inhibited the TGF-β1/Smad3 signalling pathway. (A–C) IHC and qRT-PCR indicated that the protein expression levels of TGF-β3 and Smad7 were increased while those of TGF-β1 and Smad3 were decreased in response to QL and captopril. (D) WB of p-Smad7 and p-Smad3. *p < 0.05, **p < 0.01 vs. control group. #p < 0.05, ##p < 0.01 vs. CHF group.
Figure 5.
Figure 5.
miRNA-seq data corresponding to DEmiRNAs between CHF model and QL groups. (A) Volcano plots of transformed log2 fold changes against p-values (−log10) corresponding to transcripts per million reads under both conditions examined. Green and red dots represent differentially expressed miRNAs. Black dots represent miRNAs not differentially expressed. (B) Hierarchical cluster of DEmiRNAs in the CHF vs. QL groups. Average DEmiRNA signals in each group were clustered with a Euclidean distance function. MiRNAs exhibiting similar expression patterns were clustered together (n = 5 per group). MiRNA-seq: miRNA-sequencing; DEmiRNAs: differentially expressed miRNAs.
Figure 6.
Figure 6.
Analyses of miR-345-3p, miR-328a-3p, and miR-106b-3p. (A) Expression levels of three miRNAs quantified by qRT-PCR. (B) Analysis of luciferase activity. Sequence alignment of miR-345-3p, miR-328a-3p, miR-106b-3p, and their target sites in the 3′ UTR of Smad3 wt and MUT. Normalized luciferase activities of three miRNA mimics were set to relative luciferase activity confirmed in a C. elegans negative control mimic. *p < 0.05, **p < 0.01 vs. CHF/control mimic.
Figure 7.
Figure 7.
miRNA-mRNA network constructed from three differentially expressed miRNAs confirmed by qRT-PCR.
See this image and copyright information in PMC

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