Aldehyde Metabolism and Innate Immune Signaling in Cardiovascular Disease: From Pathogenesis to Regeneration

Dear Colleagues,

Reactive aldehydes generated during metabolic and oxidative stress are now recognized as important contributors to cardiovascular disease (CVD). Molecules such as 4-hydroxy-2-nonenal, acrolein, and malondialdehyde accumulate in stressed tissues, upon binding to proteins, DNA, and other macromolecules, damage organelles, including mitochondria, proteasomes, etc., and disrupt signaling pathways that keep the heart and blood vessels healthy. Over time, these changes drive adverse cardiac remodeling, weaken contractile function, and promote vascular injury.

To counter these toxic effects, the body relies on several detoxification systems. Aldehyde dehydrogenases, aldo-keto reductases, glutathione-S-transferases, and glutathione conjugation pathways all help reduce aldehyde burden. Among them, the mitochondrial enzyme ALDH2 is especially important. Reduced ALDH2 activity due to genetic differences, chronic stress, or environmental exposures has been linked to higher aldehyde levels and increased cardiovascular risk. In contrast, the activation of ALDH2 and related pathways has been shown to lower aldehyde load, restore redox balance, and protect against tissue injury and pathophysiology.

Reactive aldehydes also act as signaling mediators that influence the immune system. They can activate inflammasomes, alter cytokine production, and recruit immune cells, fueling cycles of inflammation in heart failure, atherosclerosis, myocardial infarction, and other cardiovascular diseases. Detoxifying enzymes and antioxidant defenses help interrupt this process, limiting immune-driven injury and creating conditions that favor repair and regeneration of the myocardium and vascular tissues.

This Special Issue will explore how aldehydes, detoxifying enzymes, and immune pathways interact in cardiovascular disease. We welcome studies that define molecular mechanisms, identify biomarkers, and test therapeutic strategies. Both original research and reviews are encouraged, spanning basic science, translational models, and clinical perspectives.

Research Areas may include, but are not limited to, the following:

• Formation and accumulation of reactive aldehydes (4-hydroxy-2-nonenal, acrolein, malondialdehyde) under metabolic and oxidative stress in pathological conditions.
• Roles of detoxification systems: aldehyde dehydrogenases, aldo-keto reductases, glutathione-S-transferases, and glutathione pathways in pathophysiology as well as mitigation strategies.
• ALDH2 as a central regulator of aldehyde detoxification and cardiovascular protection
• Mechanisms linking aldehydes to mitochondrial dysfunction, impaired signaling, and cardiovascular tissue injury.
• Crosstalk between aldehyde stress and innate immune pathways, including inflammasomes and cytokine networks.
• Effects of aldehydes on immune cell activation, inflammation, and tissue repair in CVDs.
• Genetic differences in aldehyde-metabolizing enzymes and their impact on CVD risk.
• Therapeutic opportunities: pharmacological activators of ALDH2, aldehyde scavengers, and antioxidant approaches.
• Biomarkers that reflect aldehyde burden and detoxification capacity, and immune dysregulation.
• Regenerative processes influenced by aldehyde–immune interactions.

We look forward to receiving your contributions.

Dr. Suresh S. Palaniyandi
Guest Editor

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• reactive aldehydes (4-HNE, acrolein, and malondialdehyde)
• lipid peroxidation and oxidative stress
• aldehyde detoxification enzymes (ALDH2, ALDHs, AKRs, and GSTs)
• glutathione and antioxidant defense systems
• mitochondrial dysfunction and redox imbalance
• protein adducts and cellular signaling
• endothelial dysfunction and vascular injury
• inflammation, innate immunity, and inflammasomes
• cardiac remodeling, heart failure, and atherosclerosis
• biomarkers and therapeutic strategies (enzyme activators, scavengers, and regeneration)