Molecular Mechanisms of Tumor Necrosis Factor Receptor-Associated Factor 7 in Cardiac Hypertrophy

Cardiovascular System Medicine
cardiac hypertrophy TRAF7 ASK1 ubiquitination molecular mechanisms

Academic Background

Cardiac hypertrophy is a common pathophysiological process in the development of various cardiovascular diseases, such as hypertension, myocardial infarction, and congenital heart disease. Although cardiac hypertrophy is an adaptive response of the heart to adverse stimuli, long-term pathological cardiac hypertrophy can lead to severe arrhythmias and heart failure (HF). Currently, effective interventions for cardiac hypertrophy remain limited. Therefore, exploring its molecular mechanisms and identifying potential therapeutic targets are of great significance.

Tumor Necrosis Factor Receptor-Associated Factor 7 (TRAF7) is a member of the TRAF family and plays an important role in biological processes. Previous studies have shown that TRAF7 mutations are associated with congenital heart defects and malformations. However, the specific molecular mechanisms of TRAF7 in pathological cardiac hypertrophy remain unclear. Thus, this study aims to explore the molecular mechanisms of TRAF7 in cardiac hypertrophy and its potential as a therapeutic target.

Source of the Paper

This research was conducted by Yan Che, Yu-Ting Liu, and other researchers from the Department of Cardiology at Renmin Hospital of Wuhan University. The research team also included members from the Hubei Key Laboratory of Metabolic and Chronic Diseases at Wuhan University, the Department of Cardiology at Taikang Tongji (Wuhan) Hospital, and Gannan Medical University. The paper was accepted on July 14, 2024, and published online on October 7, 2024, in the journal Cardiovascular Research, titled Cardiac Tumour Necrosis Factor Receptor-Associated Factor 7 Mediates the Ubiquitination of Apoptosis Signal-Regulating Kinase 1 and Aggravates Cardiac Hypertrophy.

Research Process

1. Study Design and Animal Model Establishment

The research team first established a pressure overload-induced cardiac hypertrophy model in mice via Transverse Aortic Constriction (TAC). Additionally, cardiomyocytes were treated with Phenylephrine (PE) to induce a hypertrophic phenotype. The degree of cardiac dysfunction and remodeling was measured using echocardiography and tissue staining.

2. Exploration of Molecular Mechanisms

The research team employed various experimental methods, including RNA sequencing, Western blot, qRT-PCR, Co-Immunoprecipitation (Co-IP), and in vivo ubiquitination assays, to explore the molecular mechanisms of TRAF7 in cardiac hypertrophy. The results showed that TRAF7 expression gradually increased during the development of hypertrophy. Furthermore, TRAF7 significantly exacerbated PE-induced cardiomyocyte hypertrophy, while TRAF7 knockdown alleviated the hypertrophic phenotype.

3. In Vivo Experimental Validation

To further validate the role of TRAF7 in cardiac hypertrophy, the research team used an adeno-associated virus (AAV) to specifically overexpress TRAF7 in mouse hearts and established a TRAF7 conditional knockout mouse model. The results demonstrated that cardiac-specific overexpression of TRAF7 accelerated the hypertrophic phenotype in mice, while TRAF7 conditional knockout improved TAC-induced cardiac hypertrophy.

4. In-Depth Mechanism Analysis

The research team found that TRAF7 directly interacts with Apoptosis Signal-Regulating Kinase 1 (ASK1) and promotes its phosphorylation by mediating K63-linked ubiquitination of ASK1, thereby activating ASK1 and its downstream signaling pathways, driving the progression of cardiac hypertrophy. Notably, the pro-hypertrophic effect of TRAF7 was blocked in vitro by the ASK1 inhibitor GS4997 and in vivo by ASK1 conditional knockout.

Main Results

  1. Increased Expression of TRAF7 in Cardiac Hypertrophy: Through Western blot and immunofluorescence staining, the research team found that TRAF7 expression was significantly upregulated in TAC-induced mouse cardiac hypertrophy models and PE-induced cardiomyocytes.

  2. TRAF7 Promotes Cardiomyocyte Hypertrophy: Overexpression of TRAF7 significantly increased the hypertrophic phenotype of PE-induced cardiomyocytes, while TRAF7 knockdown inhibited this process.

  3. TRAF7 Regulates Cardiac Hypertrophy via ASK1: TRAF7 directly interacts with ASK1 and promotes its phosphorylation through K63-linked ubiquitination, thereby activating ASK1 and its downstream JNK/p38 signaling pathways.

  4. Validation with ASK1 Inhibitor and Knockout Experiments: The ASK1 inhibitor GS4997 and ASK1 conditional knockout both significantly inhibited TRAF7 overexpression-induced cardiac hypertrophy, indicating that ASK1 is a key downstream target of TRAF7 in regulating cardiac hypertrophy.

Conclusion

This study revealed that TRAF7 plays an important role in cardiac hypertrophy by mediating K63-linked ubiquitination of ASK1, promoting its phosphorylation, and activating ASK1 and its downstream signaling pathways, thereby driving the progression of cardiac hypertrophy. This discovery provides a new molecular target for the treatment of cardiac hypertrophy and suggests that modulating the TRAF7-ASK1 axis may become a novel strategy for preventing and treating cardiac hypertrophy.

Research Highlights

  1. Novel Molecular Mechanism: This study is the first to reveal that TRAF7 regulates cardiac hypertrophy through K63-linked ubiquitination of ASK1, providing new insights into the pathophysiological process of cardiac hypertrophy.

  2. Potential Therapeutic Target: The TRAF7-ASK1 regulatory axis may serve as a new therapeutic target for cardiac hypertrophy, with significant clinical application value.

  3. Multi-Level Experimental Validation: The research comprehensively validated the role of TRAF7 in cardiac hypertrophy and its molecular mechanisms through in vitro and in vivo experiments, combined with molecular and cellular biology techniques.

Research Significance

The scientific value of this study lies in revealing the new mechanism of TRAF7 in cardiac hypertrophy, providing a new perspective for the pathophysiological research of cardiac hypertrophy. Additionally, the study proposes a potential strategy for treating cardiac hypertrophy by modulating the TRAF7-ASK1 axis, which has important clinical application prospects. In the future, drug development based on this mechanism may bring new therapeutic hope to patients with cardiac hypertrophy.

Other Valuable Information

  1. Role of ROS: The study found that Reactive Oxygen Species (ROS) play an important role in the activation of TRAF7, suggesting that the ROS-TRAF7-ASK1 axis may play a key role in cardiac hypertrophy.

  2. Ubiquitination Site of ASK1: The study further identified the K1064 site of ASK1 as the key site for TRAF7-mediated K63-linked ubiquitination, providing new details on the regulatory mechanism of ASK1.

Through this study, researchers have not only deepened the understanding of the molecular mechanisms of cardiac hypertrophy but also provided important theoretical foundations for the development of new therapeutic strategies.