Investigating the potential immunoregulatory role of dimethyl malonate in myocarditis
(2026) MOBN03 20252Degree Projects in Molecular Biology
- Abstract
- Cardiovascular disease (CVD) remains the leading cause of death worldwide. Inflammation plays an important role in different CVD such as atherosclerosis and myocarditis. Myocarditis is characterized by immune cell infiltration in the myocardium. This can lead to fibrosis, cardiac remodeling, progression to dilated cardiomyopathy and heart failure. New evidence highlights the role of immunometabolism in regulating inflammatory responses. Dimethyl malonate (DMM), a competitive succinate dehydrogenase inhibitor, has shown anti-inflammatory effects in some inflammatory and ischemia-reperfusion models, however its role in myocarditis remains unclear. This study aimed to investigate the immunomodulatory effects of DMM in experimental autoimmune... (More)
- Cardiovascular disease (CVD) remains the leading cause of death worldwide. Inflammation plays an important role in different CVD such as atherosclerosis and myocarditis. Myocarditis is characterized by immune cell infiltration in the myocardium. This can lead to fibrosis, cardiac remodeling, progression to dilated cardiomyopathy and heart failure. New evidence highlights the role of immunometabolism in regulating inflammatory responses. Dimethyl malonate (DMM), a competitive succinate dehydrogenase inhibitor, has shown anti-inflammatory effects in some inflammatory and ischemia-reperfusion models, however its role in myocarditis remains unclear. This study aimed to investigate the immunomodulatory effects of DMM in experimental autoimmune myocarditis (EAM), focusing on cardiac function, fibrosis, and immune responses, as well as its impact on neutrophil ROS production. An optimized EAM model was established in A/J mice using α-myosin heavy chain peptide. Mice were treated daily with DMM or PBS from day 7 to day 35. Cardiac function was assessed by echocardiography, while fibrosis and inflammation were evaluated using histological staining. To investigate the effect of DMM on neutrophils, bone marrow-derived neutrophils were isolated from mice to assess ROS production following DMM treatment. DMM treatment did not significantly alter cardiac fibrosis, disease severity, or left ventricular ejection fraction compared to controls. Moreover, the control group only developed mild disease, which could have masked the potential effect of DMM. The in vitro experiments showed that DMM significantly reduced ROS production in stimulated neutrophils, indicating a direct immunomodulatory effect in this important innate immune cell population. In conclusion, while DMM did not improve cardiac outcomes in the EAM model in vivo, it decreased neutrophil ROS production, suggesting potential anti-inflammatory properties in vitro. The EAM model may require additional optimization to increase disease severity in controls, to be able to observe whether the immunomodulatory effects of DMM on neutrophils translate into therapeutic effects in vivo. (Less)
- Popular Abstract
- Can we control heart inflammation through metabolism?
Myocarditis is a disease where the heart becomes inflamed, which usually happens when our immune system is overactive. This inflammation can damage heart tissue and may lead to long-term heart problems. Understanding how the immune system causes this damage is important for developing new treatments.
In this project, we studied if a compound called dimethyl malonate (DMM) can reduce inflammation in the heart. DMM works by targeting how the cell produces energy, which affects how immune cells behave during inflammation. Scientists have discovered that immune cells change the way they produce energy when they become activated. One important part of this process is an enzyme called... (More) - Can we control heart inflammation through metabolism?
Myocarditis is a disease where the heart becomes inflamed, which usually happens when our immune system is overactive. This inflammation can damage heart tissue and may lead to long-term heart problems. Understanding how the immune system causes this damage is important for developing new treatments.
In this project, we studied if a compound called dimethyl malonate (DMM) can reduce inflammation in the heart. DMM works by targeting how the cell produces energy, which affects how immune cells behave during inflammation. Scientists have discovered that immune cells change the way they produce energy when they become activated. One important part of this process is an enzyme called succinate dehydrogenase (SDH), which helps produce energy inside mitochondria. When SDH activity and the availability of succinate are high, immune cells generate more free oxygen radicals or reactive oxygen species (ROS), which increase inflammation. DMM blocks SDH and has shown anti inflammatory effects in other disease models.
To test this, we used a model where mice develop myocarditis and are then treated with DMM to test if it could improve heart function. After treating the mice, we looked at their heart function, the inflammation and scarring in the heart tissue. Heart function was measured by ultrasound, and heart tissue was examined for inflammation and fibrosis. We also wanted to see the effect of DMM on immune cells in the lab, specifically cells known as neutrophils, an important type of immune cell involved in early inflammation. We isolated these cells from mouse bone marrow, to test how DMM affects their production of ROS.
Results: Our results showed that DMM did not improve heart function or reduce heart damage in the mice. This was likely because the disease in our model is mild and not all mice developed myocarditis, which made it difficult to see the treatment effects clearly. However, when we studied immune cells separately, we found that DMM reduced the production of the harmful molecules ROS which is known to contribute to inflammation and cause tissue damage.
In summary, while DMM did not improve heart function and prevent heart damage in our mouse model of mild myocarditis, it did affect how immune cells behave. This suggests that targeting cell metabolism could still be a promising approach, but more research needs to be done in models of more severe disease, to understand how and when the treatment should be applied.
Master’s Degree Project in Molecular Biology 60 credits, 2026
Department of Biology, Lund University
Advisor: Alexandru Schiopu (PI), Megan Mulholland (Postdoc)
Department of translational medicine, Lund University Clinical Research Center (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/student-papers/record/9226837
@misc{9226837,
abstract = {{Cardiovascular disease (CVD) remains the leading cause of death worldwide. Inflammation plays an important role in different CVD such as atherosclerosis and myocarditis. Myocarditis is characterized by immune cell infiltration in the myocardium. This can lead to fibrosis, cardiac remodeling, progression to dilated cardiomyopathy and heart failure. New evidence highlights the role of immunometabolism in regulating inflammatory responses. Dimethyl malonate (DMM), a competitive succinate dehydrogenase inhibitor, has shown anti-inflammatory effects in some inflammatory and ischemia-reperfusion models, however its role in myocarditis remains unclear. This study aimed to investigate the immunomodulatory effects of DMM in experimental autoimmune myocarditis (EAM), focusing on cardiac function, fibrosis, and immune responses, as well as its impact on neutrophil ROS production. An optimized EAM model was established in A/J mice using α-myosin heavy chain peptide. Mice were treated daily with DMM or PBS from day 7 to day 35. Cardiac function was assessed by echocardiography, while fibrosis and inflammation were evaluated using histological staining. To investigate the effect of DMM on neutrophils, bone marrow-derived neutrophils were isolated from mice to assess ROS production following DMM treatment. DMM treatment did not significantly alter cardiac fibrosis, disease severity, or left ventricular ejection fraction compared to controls. Moreover, the control group only developed mild disease, which could have masked the potential effect of DMM. The in vitro experiments showed that DMM significantly reduced ROS production in stimulated neutrophils, indicating a direct immunomodulatory effect in this important innate immune cell population. In conclusion, while DMM did not improve cardiac outcomes in the EAM model in vivo, it decreased neutrophil ROS production, suggesting potential anti-inflammatory properties in vitro. The EAM model may require additional optimization to increase disease severity in controls, to be able to observe whether the immunomodulatory effects of DMM on neutrophils translate into therapeutic effects in vivo.}},
author = {{Zaki, Aya}},
language = {{eng}},
note = {{Student Paper}},
title = {{Investigating the potential immunoregulatory role of dimethyl malonate in myocarditis}},
year = {{2026}},
}