GDF15 Antagonism Limits Severe Heart Failure and Prevents Cardiac Cachexia
Heart Failure (HF) is a complex disease with increasing incidence and poor prognosis. Cardiac cachexia, a common complication in HF patients, is characterized by significant weight loss, muscle wasting, and malnutrition, and its occurrence is independently associated with patient morbidity and mortality. Although cardiac cachexia is prevalent in HF patients, its pathological mechanisms remain unclear, particularly regarding the relationship between deteriorating nutritional status and worsening cardiac function.
In recent years, researchers have found that Growth Differentiation Factor 15 (GDF15), a marker of cellular stress, is significantly elevated in HF patients. GDF15 may play a key role in the development of cardiac cachexia by suppressing appetite and reducing food intake. However, the specific mechanisms of GDF15 in HF remain unclear, and there is still debate over whether it has a protective or pathogenic role.
Additionally, the role of the Integrated Stress Response (ISR) in HF has garnered widespread attention. ISR helps cells cope with various stress stimuli by regulating protein translation and transcriptional reprogramming. PPP1R15A (also known as GADD34) is a key molecule in the ISR pathway, which negatively regulates ISR activation by dephosphorylating eIF2α. However, the role of PPP1R15A in cardiac cachexia has not been fully explored.
Based on this background, this study aims to investigate the role of PPP1R15A in HF and cardiac cachexia and to explore the specific mechanisms of GDF15 in this process.
Source of the Paper
This study was conducted by a team from multiple research institutions, with primary authors including Minoru Takaoka, John A. Tadross, Ali B. A. K. Al-Hadithi, and others. The research team is affiliated with renowned institutions such as the University of Cambridge, the Spanish National Center for Cardiovascular Research (CNIC), and the University of Groningen. The paper was published online on September 23, 2024, in the journal Cardiovascular Research, with the DOI 10.1093/cvr/cvae214.
Research Process
1. Animal Model Construction and Experimental Design
The study used PPP1R15A-deficient mice (PPP1R15Aδc/δc) and wild-type mice (WT). A HF model was constructed through whole-body irradiation (11 Gy) and bone marrow transfer (BMT). After irradiation, the bone marrow cells of the mice were replaced with wild-type bone marrow cells to study the role of PPP1R15A in non-bone marrow-derived cells.
2. Cardiac Function and Body Weight Monitoring
Cardiac function was assessed using echocardiography to measure Left Ventricular Fractional Shortening (LVFS%) and Left Ventricular Mass (LVM). Body weight changes were also recorded to evaluate the severity of cardiac cachexia.
3. GDF15 Expression and Activity Detection
GDF15 expression in heart tissue was detected using Single Molecule In Situ Hybridization (SM-ISH) and real-time quantitative PCR (RT-qPCR). Additionally, ELISA was used to measure plasma GDF15 levels to assess its systemic circulation.
4. GDF15 Antagonist Experiment
To validate the role of GDF15 in cardiac cachexia, a monoclonal antibody (Mab2) was used to block GDF15 activity. Four weeks post-irradiation, PPP1R15Aδc/δc mice were randomly divided into two groups, receiving either Mab2 or IgG control antibody, with injections every three days until the end of the experiment.
5. Metabolic Parameter Detection
Metabolic parameters, including insulin, glucose, Free Fatty Acids (FFA), and corticosterone levels, were measured in plasma samples to evaluate the metabolic effects of GDF15 antagonism.
Main Results
1. PPP1R15A-Deficient Mice Exhibit Severe HF and Weight Loss
Post-irradiation, PPP1R15Aδc/δc mice showed significant declines in LVFS% and left ventricular dilation, while WT mice did not exhibit significant cardiac dysfunction. Additionally, PPP1R15Aδc/δc mice experienced significant weight loss, indicating the onset of cardiac cachexia.
2. GDF15 is Significantly Elevated in PPP1R15A-Deficient Mice
Using SM-ISH and RT-qPCR, the study found that GDF15 expression in the hearts of PPP1R15Aδc/δc mice was significantly higher than in WT mice. Furthermore, plasma GDF15 levels were also significantly elevated, suggesting that GDF15 may play a key role in cardiac cachexia.
3. GDF15 Antagonist Prevents Weight Loss and HF
Blocking GDF15 activity with Mab2 significantly slowed weight loss in PPP1R15Aδc/δc mice and improved left ventricular function. Additionally, cardiac fibrosis and plasma troponin levels were significantly reduced, indicating that GDF15 antagonism not only prevents cardiac cachexia but also slows the progression of HF.
4. Correlation Between GDF15 and Metabolic Parameters
After GDF15 antagonist treatment, insulin levels in mice increased significantly, while FFA and triglyceride levels decreased, suggesting that GDF15 may influence the progression of cardiac cachexia by regulating metabolic pathways.
Conclusions and Significance
This study is the first to reveal the critical role of PPP1R15A in HF and cardiac cachexia and to demonstrate that GDF15 is a key driver of cardiac cachexia. By blocking GDF15 activity, researchers successfully slowed the progression of HF and prevented the onset of cardiac cachexia. This discovery provides new insights into the treatment of HF, and GDF15 antagonists may become a novel therapy for severe systolic HF.
Research Highlights
First to Reveal the Role of PPP1R15A in Cardiac Cachexia: This study is the first to demonstrate that PPP1R15A-deficient mice develop severe HF and cardiac cachexia post-irradiation, providing new perspectives on the pathological mechanisms of cardiac cachexia.
GDF15 as a Key Driver of Cardiac Cachexia: The study found that GDF15 is significantly elevated in PPP1R15A-deficient mice and drives the progression of cardiac cachexia by suppressing food intake and regulating metabolic pathways.
Therapeutic Potential of GDF15 Antagonists: By blocking GDF15 activity, researchers successfully slowed the progression of HF and prevented cardiac cachexia, offering a new therapeutic strategy for HF.
Other Valuable Information
The study also found that GDF15 expression is closely related to the severity of HF in patients. By analyzing data from the BIOSTAT-CHF cohort, researchers found that plasma GDF15 levels were negatively correlated with muscle mass and protein intake in patients, further supporting the critical role of GDF15 in cardiac cachexia.
This study not only reveals the key role of GDF15 in HF and cardiac cachexia but also provides important theoretical foundations for the development of new treatments.