Genotoxic stressors, including oxidative stress, inflammation, and environmental factors are closely intertwined processes that significantly contribute to the pathogenesis of cardiovascular diseases (CVDs). These stressors can induce DNA damage, triggering mutations, chromosomal instability, and endothelial dysfunction, which are critical events in the development and progression of atherosclerosis, hypertension, and heart failure. Upon DNA damage the DNA damage response (DDR) activates a network of signaling molecules that can influence immune cell function, cytokine production, and the activation of inflammatory pathways.
Autophagy and efferocytosis are two key cellular processes involved in cellular survival and metabolic response to genotoxic stressors. Those mechanisms play a crucial role in maintaining cellular homeostasis by degrading damaged components, including misfolded proteins, organelles, and lipids. Importantly, both pathways are intimately linked to the DDR in CVDs, influencing both the repair of damaged cells and the resolution of inflammation. In cardiovascular tissues, compromised autophagic function due to DDR failure can lead to the persistence of dysfunctional cellular components, increasing oxidative stress and contributing to endothelial dysfunction and atherosclerosis.
Similarly, efferocytosis, which clears apoptotic cells from the vascular wall, is influenced by DDR signaling. When cells undergo apoptosis due to DNA damage, proper clearance by macrophages prevents the release of harmful pro-inflammatory signals that could exacerbate CVD. Defective efferocytosis, often due to impaired DDR signaling, can lead to the accumulation of dying cells in atherosclerotic plaques, triggering chronic inflammation and plaque instability. In addition to its role in mitigating inflammation, autophagy directly influences the cell’s ability to repair DNA damage. For example, autophagy provides resources necessary for the DNA repair process, including energy and precursors for nucleotide synthesis, and the regulation of the cGAS-STING pathway. When autophagy is deficient, DNA damage accumulates, fueling further inflammatory activation through pathways like NF-κB.
Additionally, DDR signaling can influence the activation of pattern recognition receptors (PRRs) in immune cells, linking DNA damage to innate immunity. The interplay between DDR and immune responses also involves the release of damage-associated molecular patterns (DAMPs), which further promote inflammation and immune activation. Epigenetic modifications, such as changes in DNA methylation, histone modifications, and non-coding RNA expression, can influence the DDR and inflammatory responses, creating long-lasting effects on immune cell function. These epigenetic changes may also affect the resolution of inflammation, thereby influencing chronic inflammatory conditions like atherosclerosis and autoimmune diseases, with potential implications for CVD.
Despite this understanding, significant gaps remain in the mechanistic links between genotoxic stressors, survival pathways, and inflammation. In addition, it is still controversial the contribution of selective inflammatory sub-populations, as well as their mechanism of recruitment and differentiation according to a selective stressor. Current research suggests that targeting survival pathways may present new therapeutic avenues to prevent damage-induced inflammation and its associated cardiovascular outcomes.
In this Research Topic, we welcome the submission of manuscripts that cover recent advances in the following areas:
• Immune cell subset differentiation and tissue inflammation under genotoxic stressors. • Metabolic pathways involved in inflammation in CVD, with a specific immunological focus. • Survival mechanisms against inflammation in CVD, with a specific immunological focus. • Genotoxic damage in inflammatory cells in CVD, with a specific immunological focus. • Novel therapeutic interventions against genotoxic insults mediating the inflammatory activation contributing at CVD progression. • Novel therapeutic interventions modulating non-coding RNAs against genotoxic insults mediating the inflammatory activation contributing at CVD progression.
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