Abstract
Background
Postinfarction cardiac remodeling presents a compensatory mechanism aimed at mitigating congestive heart failure. It is distinguished by progressive dilatation and hypertrophy of the ventricular chambers, fibrotic alterations, and prolonged apoptosis of cardiomyocytes. The primary objective of this study was to assess the effects of icariin on myocardial fibrosis and ventricular remodeling in rats subjected to myocardial infarction (MI).
Methods
Male Sprague‒Dawley (SD) rats were subjected to randomization and subsequently divided into distinct groups: the control group, the sham group (undergoing sham operation), the MI group (experiencing ligation of the left anterior descending artery), and the icariin group. Within the icariin group, rats were further categorized into three different dose groups based on the administered icariin dosage: the MI30 group (30 mg/kg/day), the MI60 group (60 mg/kg/day), and the MI120 group (120 mg/kg/day). Cardiac function evaluation was carried out using echocardiography. Histological examinations, including hematoxylin and eosin (HE) staining, Masson staining, and immunohistochemistry studies, were conducted 90 days after the occurrence of MI. Additionally, Western blotting was employed to assess TGF‐β1, p-Smad2, and p-Smad3 levels.
Results
The administration of icariin revealed a noteworthy enhancement in cardiac function among rats afflicted with left anterior descending coronary artery (LAD) ligation. In comparison to the icariin groups, the MI group exhibited reduced EF and FS, along with elevated LVEDD and LVESD. Furthermore, the cardiac fibrosis levels in the MI group rats exhibited a considerable increase compared to those in the icariin group. Notably, the levels of Collagen I, Collagen III, MMP2, and MMP9 were significantly higher in the MI group than in the icariin group, with evident distinctions. Moreover, the expression levels of TGF-β, IL-13, p-Smad2, and p-Smad3 were notably upregulated in the MI group compared to the icariin group.
Conclusions
In an experimental rat model of MI, the administration of icariin resulted in the amelioration of both cardiac function and remodeling processes, operating through the intricate TGF-β1/Smad signaling pathway.
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Introduction
As the standard of living steadily improves, the aging population is on the rise, and myocardial infarction (MI) stands as the foremost contributor to both morbidity and mortality within the realm of cardiovascular diseases worldwide [1]. While modern reperfusion therapy serves as the most efficacious approach for diminishing infarct size and ameliorating clinical outcomes after MI, heart failure remains the primary cause of death subsequent to MI. The process of heart remodeling following MI is acknowledged as the initial phase leading toward heart failure [2, 3]. Consequently, the reversal of ventricular remodeling emerges as a highly desirable prospect for the treatment of MI. Certain angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), when administered as long-term treatment, have demonstrated the capacity to attenuate ventricular remodeling [4,5,6]. However, a significant number of patients encounter intolerance to ACEIs/ARBs due to conditions such as renal dysfunction, hypotension, or hyperkalemia, among others. Hence, there exists considerable interest in identifying novel therapeutic agents capable of enhancing ventricular remodeling, thereby addressing this pressing concern.
Myocardial fibrosis and ventricular remodeling have been identified as crucial pathological factors contributing to unfavorable outcomes following MI [7]. Of notable significance, the TGF‐β1/Smad signaling pathway exhibits a close association with both myocardial fibrosis and ventricular remodeling [8, 27,28,29]. TCM compounds are known to comprise a diverse array of Chinese medicinal ingredients that act through various targets, channels, and pathways to address diseases. Among these, icariin, the primary active ingredient derived from the Chinese herbal medicine Epimedium brevicornu Maxim, has garnered considerable interest [30, 31]. Several species of Epimedium can be used to extract it, including Epimedium sagitta, Epimedium pilose, Epimedium Wushan, and Epimedium korean. Icariin has been shown to protect the myocardium from ischemia and reperfusion in previous studies [32,33,34,35]. Icariin has a therapeutic effect on coronary heart disease, but its mechanism remains largely unclear. According to TCM principles, ventricular dysfunction and heart failure arise from Qi deficiency and blood stasis [36, 37]. In this study, icariin therapy exhibited notable improvements in LVEF and FS while concurrently reducing LVEDD and LVESD compared to the MI group. Moreover, this study sheds light on the hitherto unexplored function and mechanism of icariin in mitigating cardiac fibrosis.
The TGF-β1/Smad signaling pathway assumes a pivotal role in cardiac fibrosis and ventricular remodeling [38]. This study sought to quantify the changes in the expression levels of key molecules within the TGF-β1 signaling pathway. Notably, following MI, there was evident overexpression of TGF-β1 in the myocardium, whereas treatment with icariin resulted in a significant reduction in TGF-β1 in the ischemic myocardium. To validate this hypothesis, Western blotting was performed on M2-type macrophages induced by IL4, revealing that icariin supplementation led to decreased levels of TGF-β1 and Smad2/3. Presently, research concerning the antitumor activity of icariin has emerged as a prominent area of interest. These findings demonstrate that icariin effectively inhibits M2 macrophage polarization, signifying its potential to modulate the tumor microenvironment. Prior studies have already established icariin's ability to inhibit M2 macrophage polarization while promoting M1 macrophage polarization [18, 39]. There is still work to be done to determine whether icariin affects myocardial fibrosis and ventricular remodeling by regulating macrophage polarization.
In conclusion, the present study provides compelling evidence that icariin significantly reduces cardiac fibrosis and ameliorates cardiac function in rats with myocardial infarction. The potential protective effects of icariin are closely associated with modulation of the TGF-β1/Smad signaling pathway. However, it is essential to acknowledge certain limitations within this study. First, the follow-up period for the MI rats was relatively short, thereby precluding the observation of long-term changes in cardiac function. Second, given the intricate molecular mechanisms involved, the precise mechanisms through which icariin confers protective effects on cardiac fibrosis remain incompletely elucidated. Thus, further investigations are warranted to validate and expand upon the present findings.
Limitations of the study
Firstly, the selection of icariin dosage in our study was based on a review of pertinent literature. However, it is noteworthy that there is a dearth of dose–response investigations aimed at determining the most efficacious icariin dosage for achieving optimal outcomes. Additionally, comprehensive long-term safety evaluations for icariin treatment are presently lacking. Secondly, we did not employ TTC staining to validate the myocardial infarction's extent. Lastly, it should be acknowledged that this study was characterized by a limited sample size, an absence of power calculations, and the potential influence of uncontrolled confounding variables.
Conclusion
The findings of the current study suggest that icariin possesses the capacity to enhance cardiac function and mitigate ventricular remodeling in rats following MI. These results underscore icariin's potential as a viable therapeutic target for addressing myocardial injury and ventricular remodeling.
Availability of data and materials
All data and materials utilized in this study are accessible upon reasonable request from the corresponding author.
Abbreviations
- MI:
-
Myocardial infarction
- LAD:
-
Left anterior descending coronary artery
- LVEDD:
-
Left ventricular end-diastolic diameter
- LVESD:
-
Left ventricular end-systolic diameter
- FS:
-
Left ventricular shortening fraction
- EF:
-
Left ventricular ejection fraction
- ACEI:
-
Angiotensin-converting enzyme inhibitors
- ARB:
-
Angiotensin receptor blockers
- RAAS:
-
Renin–angiotensin–aldosterone system
- MMPs:
-
Matrix metalloproteinases
- TCM:
-
Traditional Chinese medicine
- ELISA:
-
Enzyme-linked immunosorbent assay
- SD:
-
Sprague–Dawley
- H&E:
-
Hematoxylin and eosin
- DMSO:
-
Dimethyl sulfoxide;
- ANOVA:
-
One-way analysis of variance
- TGF-β:
-
Transforming growth factor beta
- ECM:
-
Matrix metalloproteinases
- p‐Smad2:
-
Phosphorylated Smad2
- p‐Smad2:
-
Phosphorylated Smad3
- LV:
-
Left ventricular
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Funding
This research was supported by the Science Research Foundation of Yunnan Provincial Department of Education Project (NO. 2022J0017), Medical Reserve Talent Training Program of Yunnan Provincial Health Commission of China (NO. H-2017019), and Yunnan Provincial Program for the Cultivation of High-level Innovative Health Talent (NO. YNWR-MY-2020-024).
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The study was conceptualized by Ji Jia, **ng-an Zhao, Si-ming Tao, and Jun-wen Wang. The experimentation was conducted by Ji Jia, **ng-an Zhao, Si-ming Tao, Rong-liang Zhang, and **-tao Li. Ji Jia, **ng-an Zhao, and Si-ming Tao made significant contributions to the data analysis and manuscript preparation. Ji Jia and Si-ming Tao performed the data analyses and authored the manuscript. Hua-lei Dai, **n-** Zhang, Ming-hua Han, Bei Yang, and Yu Li provided constructive discussions and assistance during the analysis process.
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The ethics committee of the Animal Research Committee of the Yunnan University College of Medicine reviewed and approved the study (approval number YNU20220333).
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Jia, J., Zhao, Xa., Tao, Sm. et al. Icariin improves cardiac function and remodeling via the TGF-β1/Smad signaling pathway in rats following myocardial infarction. Eur J Med Res 28, 607 (2023). https://doi.org/10.1186/s40001-023-01588-4
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DOI: https://doi.org/10.1186/s40001-023-01588-4