Injection of Matrix Metalloproteinase-9 Leads to Ventricular Remodeling
Enzheng Zhu1, Congcong Yuan1, Simiao Hu1
1Department of Cardiology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangdong Province, 510080, China.
Objective:
Previous studies have found that some ventricular remodeling is accompanied by increased matrix metalloproteinase-9 (MMP-9) in vivo, and MMP-9 inhibitors can reduce ventricular remodeling. However, there is still no direct evidence that MMP-9 causes ventricular remodeling. In this study, MMP-9 was injected into rats to observe whether MMP-9 caused ventricular remodeling, thereby providing direct evidence of MMP-9-induced ventricular remodeling.
Methods:
Forty-eight eight-week-old male Wistar rats were randomly divided, by weight, into control, low-, medium-, and high-dose MMP-9 groups and were administered normal saline or recombinant rat MMP-9 0.7, 1.4, or 2.1 ng/g, respectively, via intraperitoneal injection, twice per week. On the 28th day, six rats were randomly selected from each group (Stage I). The remaining rats continued receiving injections until the 56th day (Stage II). Echocardiography was performed to observe cardiac structure and function, and the left ventricular mass index (LVWI) was calculated. Myocardial pathological changes and the collagen volume fraction (CVF) were observed by HE and VG staining in myocardial tissue. MMP-9 levels in serum were tested using ELISA. Myocardial MMP-9 levels were measured using Western blots, and the myocardial expression levels of MMP-9 mRNA were assessed using RT-PCR.
Results:
During Stage I, serum MMP-9 and myocardial MMP-9 mRNA levels are increased; hypertrophic cardiomyocytes, disorderly arrangement of fibers, and endochylema dissolution are observed in the medium- and high-dose groups. The left ventricular weight index (LVWI) and myocardial MMP-9 increased, and the collagen volume fraction (CVF) reduced in the high-dose group. In Stage II, the left ventricular end-diastolic volume (LVEDV) and diameter (LVIDd) are higher, and CVF decreased in the medium- and high-dose groups. Myocardial pathological lesions intensified. Serum MMP-9 in the model groups and myocardial MMP-9 in the medium- and high-dose groups are increased.
Conclusions:
Injection of MMP-9 can lead to ventricular remodeling.
Insights
Matrix metalloproteinase-9 (MMP-9) directly causes ventricular remodeling in rats. This study provides evidence that elevated MMP-9 levels lead to cardiac structural and functional changes, indicating its causative role in ventricular remodeling.
Area of Science:
- Cardiovascular Research
- Molecular Biology
- Pathology
Background:
- Ventricular remodeling is associated with increased matrix metalloproteinase-9 (MMP-9) in vivo.
- MMP-9 inhibitors have shown potential in reducing ventricular remodeling.
- Direct evidence linking MMP-9 to the causation of ventricular remodeling is lacking.
Purpose of the Study:
- To investigate whether direct injection of MMP-9 induces ventricular remodeling in rats.
- To provide direct evidence for MMP-9-induced ventricular remodeling.
Main Methods:
- Male Wistar rats received intraperitoneal injections of varying doses of MMP-9 or saline twice weekly for up to 56 days.
- Cardiac structure and function were assessed using echocardiography and left ventricular weight index (LVWI).
- Histopathological analysis (HE, VG staining) and molecular assessments (ELISA, Western blot, RT-PCR) were performed on myocardial tissue and serum.
Main Results:
- Increased serum MMP-9 and myocardial MMP-9 mRNA were observed in Stage I.
- Medium- and high-dose MMP-9 groups showed hypertrophic cardiomyocytes, disorganized fibers, and increased LVWI, with reduced collagen volume fraction (CVF) in the high-dose group.
- In Stage II, higher left ventricular dimensions and reduced CVF were noted in medium- and high-dose groups, with intensified pathological lesions.
Conclusions:
- Direct injection of MMP-9 can induce ventricular remodeling.
- MMP-9 plays a direct causative role in the development of ventricular remodeling.
- These findings establish MMP-9 as a key mediator in ventricular remodeling processes.
