Cardiovascular diseases (CVD), such as hypertension and myocardial infarction, are among the most common causes of death worldwide. A central feature of these diseases is the inflammatory response to heart damage, which is mediated by immune cells such as neutrophils, macrophages and T lymphocytes. Recent research suggests that immune metabolism – the metabolic reprogramming of immune cells – is critical to their function in the inflammatory response and tissue repair following cardiac injury.
(red) A key role in this process could be played by extracellular vesicles (EVs), which serve as a means of transport for bioactive molecules such as microRNAs (miRNAs) and enable communication between cells and organs.
The role of immunometabolism in cardiac injury and remodeling
Immune cells are crucial for the inflammatory response after heart damage and make a significant contribution to healing. While only a few immune cells are present in a healthy heart, their number increases considerably after an injury due to cells that mainly originate from the spleen. These cells perform important tasks such as phagocytosis of dead cells and coordination of vascular and tissue remodeling.
Metabolic reprogramming of immune cells plays a crucial role in their function. Inflammatory subtypes of immune cells, such as M1-like macrophages and Th1/Th17 cells, rely predominantly on glycolysis as an energy source, especially under hypoxic conditions such as occur in the ischemic heart. Anti-inflammatory and reparative subtypes, such as M2-like macrophages and Treg cells, on the other hand, rely more on mitochondrial oxidative phosphorylation (OXPHOS). This distinction between metabolic pathways is crucial for the function of immune cells during the inflammatory response and healing processes.
Extracellular vesicles in heart health and disease
While immunometabolism plays a key role in the response to cardiac injury, little is known about the mechanisms that control metabolic reprogramming of immune cells. Extracellular vesicles (EVs) may play an important role here. EVs are membrane-enveloped vesicles that are released by cells and transport bioactive molecules such as proteins, lipids, DNA and RNAs. They can act as endocrine signaling molecules and are therefore potentially promising therapeutic agents.
There is increasing evidence that EVs play an important role in the communication between cells of the cardiovascular system and can mediate both health-promoting and damaging effects. In various models of myocardial infarction (MI), an increase in circulating EVs has been observed, which could serve as a marker for the extent of damage. For example, EVs from necrotic cardiomyocytes are taken up by phagocytic monocytes and trigger the release of inflammatory cytokines such as IL-6, CCL2 and CCL7, further enhancing the inflammatory response.
The role of EVs in intercellular communication after cardiac injury
EVs play an important role in the interaction between different cell types in the heart, especially after an injury. For example, after a heart attack, endothelial cells release increased amounts of EVs, which trigger inflammatory and migratory reactions in monocytes. These monocytes are then mobilized from the spleen to migrate to the injured site and act there. However, these mechanisms can also be detrimental, as EVs from diabetic endothelial cells can impair angiogenesis and re-vascularization after MI.
In addition, EVs produced by macrophages exposed to a hyperglycemic environment (as in diabetes) have been shown to trigger increased collagen production in fibroblasts and thus contribute to cardiac fibrosis. EVs from CD4+ T cells containing miR-142-3p also exacerbate the consequences of MI by increasing infarct size and impairing cardiac function. These studies highlight the central role of EVs in the pathophysiology of heart disease and their involvement in the interaction between different cell types in the heart.
Interorgan communication through EVs in cardiac injury and cardioprotective mechanisms
EVs are not only involved in communication between cells within the heart, but can also transmit signals between different organs. Studies in transgenic animals have shown that EVs produced in the heart during heart failure can be detected in the brain, where they contribute to increased sympathetic excitation. This underlines the importance of EVs in systemic communication in cardiovascular disease.
White adipocytes (WAT) are an important source of EVs with potential cardiotoxic effects. EVs from WAT of obese mice induce macrophage activation, which may exacerbate cardiometabolic complications. These EVs carry miRNAs that may amplify inflammatory signaling and thus contribute to cardiac injury. In contrast, EVs from brown adipose tissue (BAT) appear to have cardioprotective properties. EVs from BAT released after exercise contain cardioprotective miRNAs that can inhibit cardiomyocyte apoptosis after ischemia-reperfusion (I/R) injury. These results suggest that EVs from different sources may exert both deleterious and protective functions in the heart.
The interaction of EVs and immune metabolism in cardiac injury
There is preliminary evidence that EVs play a role in the metabolic reprogramming of immune cells following cardiac injury. Different EV cargos may contribute to the polarization of macrophages towards inflammatory or anti-inflammatory phenotypes. For example, EVs from macrophages in a pro-inflammatory environment contain certain miRNAs that promote glycolysis and enhance inflammatory responses. Other EVs, however, transport miRNAs and proteins that promote oxidative phosphorylation (OXPHOS) in macrophages and thus enhance anti-inflammatory signals.
Some EVs also transport enzymes that are involved in fatty acid oxidation and can thus activate anti-inflammatory metabolic pathways in immune cells. These enzymes could potentially be used to treat cardiovascular diseases as they support the reprogramming of immune cells into an anti-inflammatory state.
Challenges and future prospects
Although EVs have great potential as therapeutic agents, many challenges remain. The exact mechanics of how EVs affect specific immune cells is still unclear. In addition, EVs often carry a variety of molecules whose exact effects on target cells are not yet fully understood. Another challenge is the short half-life of EVs in the bloodstream, which may affect dose efficiency and potential off-target effects.
Future studies should focus on better understanding the mechanisms of EV biogenesis, the sorting of their cargo and the specific uptake by cells. Such findings could pave the way for new therapies that exploit the potential of EVs to treat cardiovascular diseases.
Conclusion
Insights into immunometabolism and the role of EVs in cardiovascular health and disease are expanding our understanding of the complex interactions between immune cells, metabolic pathways and the heart. The ability of EVs to transport bioactive molecules across organ and cell boundaries makes them a promising target for future therapeutic approaches for the treatment of cardiovascular diseases.
Source: Omoto ACM, do Carmo JM, da Silva AA, et al: Immunometabolism, extracellular vesicles and cardiac injury. Front Endocrinol (Lausanne). 2024 Jan 8; 14: 1331284. doi: 10.3389/fendo.2023.1331284. PMID: 38260141; PMCID: PMC10800986.
CARDIOVASC 2024; 23(3): 39-40
