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Updated: Jan 8, 2026
Acute Myocardial Infarction in Rats
Published on: February 16, 2011
RBM25 Regulates p38 MAPK Pathway Activation via Exon 16 Skipping of MAP4K4 in a Rat Model of Post-Infarction Heart
Hao Li1, Keyi Zhang1, Chen Liu2
1Cardiovascular Clinical Medicine Center The First Affiliated Hospital of Kunming Medical University Kunming China.
Abstract:
Ischemic cardiomyopathy remains a leading cause of heart failure (HF), yet its molecular mechanisms remain incompletely defined. This study aimed to identify the RNA-binding protein 25(RBM25) as a critical regulator of HF progression through MAP4K4 alternative splicing and p38 MAPK pathway activation. A left anterior descending (LAD) coronary artery ligation-induced HF model was established in Sprague-Dawley (SD) rats, with pericardial delivery of lentiviral vectors for RBM25 overexpression (OE-RBM25) or shRNA-mediated knockdown (sh-RBM25). Quantitative PCR (qPCR) experiments confirmed that overexpression of RBM25 induces exon 16 skipping in MAP4K4. Computational modeling further predicted that the resulting variant enhances binding to MAP3K1 and potentially activates the MAPK pathway. Cardiac function, infarct size, apoptosis, and molecular markers were evaluated via echocardiography, TTC staining, ELISA, qPCR, Western blot, and TUNEL assays. RBM25 overexpression significantly increased myocardial infarction area compared to the HF control group (p < 0.01), while RBM25 knockdown reduced infarct size (p < 0.01). Consistently, RBM25 overexpression upregulated pro-apoptotic markers (Caspase-3, Bax; p < 0.05) and downregulated anti-apoptotic Bcl-2 (p < 0.05), whereas RBM25 inhibition reversed these effects. Mechanistically, RBM25 induced exon 16 skipping in MAP4K4, generating a truncated isoform that activated MAPK signaling, as evidenced by increased phosphorylation of ERK (p < 0.05) and elevated downstream effectors (C-FOS, EGR1, PARP1; p < 0.05). P38 MAPK inhibition (SB203580) attenuated RBM25-mediated myocardial injury, while agonist-induced MAPK activation (Gambogic Amide) abolished the protective effects of RBM25 knockdown. These findings suggest that RBM25 exacerbates HF through MAP4K4 splicing-dependent p38 MAPK activation, highlighting its potential as a therapeutic target for ischemic cardiomyopathy.
Insights
RNA-binding protein 25 (RBM25) exacerbates heart failure (HF) by activating the p38 MAPK pathway through MAP4K4 alternative splicing. Inhibiting RBM25 may offer a therapeutic strategy for ischemic cardiomyopathy.
Area of Science:
- Cardiovascular Biology
- Molecular Mechanisms of Disease
- RNA Biology
Background:
- Ischemic cardiomyopathy is a major cause of heart failure (HF), but its underlying molecular mechanisms are not fully understood.
- Identifying key regulators of HF progression is crucial for developing effective therapies.
Purpose of the Study:
- To investigate the role of RNA-binding protein 25 (RBM25) in the progression of ischemic cardiomyopathy.
- To elucidate the molecular mechanisms by which RBM25 influences HF, specifically focusing on MAP4K4 alternative splicing and p38 MAPK pathway activation.
Main Methods:
- Established a rat model of ischemic cardiomyopathy via LAD ligation.
- Utilized lentiviral vectors for RBM25 overexpression and knockdown.
- Performed qPCR, echocardiography, TTC staining, ELISA, Western blot, and TUNEL assays.
- Investigated the effects of p38 MAPK inhibition and activation.
Main Results:
- RBM25 overexpression increased myocardial infarction size and apoptosis, while RBM25 knockdown reduced infarct size.
- RBM25 induced MAP4K4 exon 16 skipping, leading to truncated isoform formation.
- Activated the p38 MAPK pathway, evidenced by increased ERK phosphorylation and downstream effector expression.
- Pharmacological inhibition of p38 MAPK attenuated RBM25-induced myocardial injury.
Conclusions:
- RBM25 exacerbates ischemic cardiomyopathy by promoting MAP4K4 alternative splicing and activating the p38 MAPK pathway.
- RBM25 represents a potential therapeutic target for treating ischemic cardiomyopathy.
