Xinfuli Granule improves post-myocardial infarction ventricular remodeling and myocardial fibrosis in rats by regulating TGF-β/Smads signaling pathway.

Q: What are the key findings of this study?

High-dose Xinfuli Granule significantly reduced the myocardial infarct collagen area compared to untreated MI rats (25.72 ± 4.18 vs 44.54 ± 10.91, P < 0.01) and regulated TGF-β/Smads signaling.

Q: What is the clinical evidence from this study?

Population: Acute myocardial infarction (AMI) with ventricular remodeling and myocardial fibrosis in a rat model (n=75). Intervention: Xinfuli Granule (XG) vs. Untreated MI model (normal saline), sham control (normal saline), and carvedilol (10 mg/kg/day). Primary outcome: Myocardial collagen area in the infarction area (Masson staining 100x, high-dose XG vs MI control) (p=<0.01).

Q: What question did this study set out to answer?

To investigate the effects and underlying molecular mechanisms of Xinfuli Granule on ventricular remodeling and myocardial fibrosis in rats following acute myocardial infarction.

Jie Ma; Zhiyuan Li; Xiaopeng Liang; Caixia Guo; Peipei Lu; Lihong Ma

doi:10.11909/j.issn.1671-5411.2017.05.005

May 1, 2017

Xinfuli Granule improves post-myocardial infarction ventricular remodeling and myocardial fibrosis in rats by regulating TGF-β/Smads signaling pathway.

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Key result

High-dose Xinfuli Granule reduces myocardial infarct collagen area ~42% in post-MI rats.

P<0.01
n=75

Figures

Why the study?

While clinical and experimental studies confirmed the effects of Xinfuli Granule in heart failure, its effects and mechanisms on ventricular reconstruction after acute myocardial infarction required investigation.

Does Xinfuli Granule improve post-myocardial infarction ventricular remodeling and inhibit myocardial fibrosis by regulating the TGF-β/Smads signaling pathway in rats with acute myocardial infarction?

Key Points

To investigate the effects and underlying molecular mechanisms of Xinfuli Granule on ventricular remodeling and myocardial fibrosis in rats following acute myocardial infarction.
Sprague-Dawley rats underwent left anterior descending coronary artery ligation and were randomized into five post-infarction groups: medium-dose Xinfuli Granule (1.50 mg/kg/day, n=13), high-dose Xinfuli Granule (3.00 mg/kg/day, n=12), carvedilol (10 mg/kg/day, n=12), combined medium-dose Xinfuli Granule and carvedilol (n=13), and untreated model control (n=11), alongside sham-operated rats (n=14).
Treatments were administered via daily oral gavage for 28 consecutive days beginning 24 hours after model induction.
At day 28, cardiac function was assessed by echocardiography, ventricular hypertrophy by weight ratios (HW/BW, LVW/BW), collagen deposition by Masson and Sirius red staining, and TGF-β/Smads signaling proteins by Western blot, immunohistochemistry, and immunofluorescence.
Medium-dose Xinfuli Granule significantly reduced LVIDS (P < 0.01), HW/BW (P < 0.05), non-infarct type I/III collagen ratio (P < 0.01), and myocardial collagen fraction (P < 0.01), while significantly increasing LVFS (P < 0.05) and LVW/BW compared with other groups.
Treatment with Xinfuli Granule or carvedilol significantly decreased expression of Smad3, P-Smad3, and Smad2 proteins and significantly increased Smad7 expression compared with the untreated infarction group (all P < 0.01).

Structured PICO

Does Xinfuli Granule improve post-myocardial infarction ventricular remodeling and inhibit myocardial fibrosis by regulating the TGF-β/Smads signaling pathway in rats with acute myocardial infarction?

P

Population

75 male Sprague-Dawley rats (weighing 200 ± 20 g) with experimentally-induced acute myocardial infarction (LVEF < 60%) or sham surgery, followed for 28 days.

I

Intervention

Xinfuli Granule (XG) administered via oral lavage once daily for 28 consecutive days in medium-dose (1.50 mg/kg/day, n=13), high-dose (3.00 mg/kg/day, n=12), or medium-dose combined with carvedilol 10 mg/kg/day (n=13).

C

Comparator

MI model control group receiving equivalent normal saline (10 mL/kg/day, n=11), positive control group receiving carvedilol 10 mg/kg/day via lavage (n=12), and sham-operated control group receiving normal saline (n=14).

O

Outcome

Ventricular remodeling and myocardial fibrosis parameters at 28 days, including echocardiographic parameters (LVEF, LVFS, LVIDS), heart and left ventricular weight ratios (HW/BW, LVW/BW), myocardial collagen area in the infarction zone (Masson staining), type I/III collagen ratio (Sirius red staining), and TGF-β/Smads pathway protein expression (Smad3, P-Smad3, Smad2, Smad7).surrogate

Main Result

Absolute Event Rate: 25.72% vs 44.54%

p-value: p=<0.01

Xinfuli Granule attenuates post-infarction ventricular remodeling and myocardial fibrosis in rats at least in part by inhibiting the pro-fibrotic TGF-β/Smads signaling pathway.

Limitations

Preclinical animal model (Sprague-Dawley rats)
The combination of medium-dose XG and carvedilol was not superior to the single application of carvedilol, which remains to be further studied
Immunohistochemical staining and immunofluorescence used to confirm Smad3 expression were noted as not flawless
Preclinical rat model study
Combination of medium-dose XG and carvedilol was not superior to carvedilol alone and requires further study
Immunohistochemical staining and immunofluorescence confirmation of Smad3 were noted by authors as not flawless

Implication

Supports post-MI antifibrotic effects in rats; hypothesis-generating for TGF-β/Smads modulation and requires clinical trials before any human application.

Abstract

Background Recent clinical and experimental studies have confirmed the effects of Xinfuli Granule (XG), a compound Chinese medicine in the prevention and treatment of heart failure (HF). This study aimed to investigate the effects and the mechanisms of XG on ventricular reconstruction in rats with acute myocardial infarction (AMI). Methods Sprague-Dawley rats were subjected to left anterior descending branch ligation. The rats that survived 24 h were randomly assigned to five groups: medium-dose of XG group (MI+XGM), high-dose of XG group (MI+XGH), carvedilol group (MI+C), medium-dose of XG + carvedilol group (MI+C+XGM). Fourteen rats underwent identical surgical procedures without artery ligation, serving as sham controls. At 28 days, left ventricular weight to body weight (LVW/BW) and heart weight to body weight (HW/BW) were calculated; left ventricular ejection fraction (LVEF), left ventricular shortening fraction (LVFS), left ventricular internal diameter at systole (LVIDS) were measured by ultrasound; HE staining, Masson staining, and Sirius red staining were used to assess the myocardial pathological and physiological changes as well as myocardial fibrosis area and non-infarct zone I/III collagen ratio. Expression of Smad3 were detected and analyzed by Western blot, immunohistochemistry and immunofluorescence. P-Smad3, Smad2 and Smad7 in the TGF-β/Smads signaling pathway were also analyzed by Western blot. Results The LVIDS (P < 0.01), HW/BW (P < 0.05), type I/III collagen ratio (P < 0.01) and myocardial collagen (P < 0.01) decreased significantly while the LVW/BW, LVFS (P < 0.05) increased significantly in MI+XGM group as compared with those in other groups. The expression of key signal molecules of the TGF-β/Smads signaling pathway, including Smad3, P-Smad3 and Smad2 protein were decreased, while the expression of Smad7 increased in both XG and carvedilol treatment groups as compared to those of the MI group (all P < 0.01). Immunohistochemistry and immunofluorescence further confirmed the down-regulated Smad3 expression. Conclusion XG can improve ventricular reconstruction and inhibit myocardial fibrosis in rats with AMI by regulating TGF-β/Smads signaling pathway.

Discussion

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Cite This Study

Ma et al. (2017) studied Acute myocardial infarction (AMI) with ventricular remodeling and myocardial fibrosis in a rat model (n=75). Xinfuli Granule (XG) vs. Untreated MI model (normal saline), sham control (normal saline), and carvedilol (10 mg/kg/day) was evaluated on Myocardial collagen area in the infarction area (Masson staining 100x, high-dose XG vs MI control) (p=<0.01). High-dose Xinfuli Granule significantly reduced the myocardial infarct collagen area compared to untreated MI rats (25.72 ± 4.18 vs 44.54 ± 10.91, P < 0.01) and regulated TGF-β/Smads signaling.

synapsesocial.com/papers/6a707d30c1a24a6142db8606 https://doi.org/10.11909/j.issn.1671-5411.2017.05.005

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Xinfuli Granule improves post-myocardial infarction ventricular remodeling and myocardial fibrosis in rats by regulating TGF-β/Smads signaling pathway.

Figures

Key Points

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

Xinfuli Granule improves post-myocardial infarction ventricular remodeling and myocardial fibrosis in rats by regulating TGF-β/Smads signaling pathway.

Figures

Key Points

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

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