The Role of Inflammation and Immunity in Cardiovascular Disease: Molecular Mechanisms and Therapeutic Targets

Figures

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  FIGURE 1. Immune landscape and representative inflammatory signaling networks in cardiovascular diseases. Pathological stressors trigger the release of DAMPs, which activate the TLR, cGAS–STING, and NLRP3 inflammasome axes in cardiovascular tissues. These interconnected pathways drive inflammatory priming, Type I interferon and cytokine responses, caspase‐1 activation, and pyroptosis, while being shaped by immunometabolic regulation. Collectively, they contribute to endothelial activation, plaque formation, hypertrophy, fibrosis, and adverse cardiovascular outcomes.

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  FIGURE 2. Multifaceted mechanisms of mitophagy activation. Damaged mitochondria are selectively recognized and eliminated through multiple pathways. PINK1/Parkin‐dependent pathway: Upon OMM depolarization, PINK1 accumulates and recruits Parkin, which ubiquitinates mitochondrial proteins. Ubiquitin‐binding adaptors (e.g., p62, NBR1, OPTN, NDP52, TAX1BP1) interact with LC3 to initiate phagophore formation. Receptor‐mediated pathways: OMM proteins such as BNIP3, NIX, FUNDC1, FKBP8, and BCL2L13 harbor LC3‐interacting regions and directly recruit damaged mitochondria to autophagosomes. Lipid and protein signals: Cardiolipin externalization to the OMM facilitates LC3 binding; IMM/mitochondrial matrix proteins such as PHB2 and NLRX1 also participate in recognition. Ceramide signaling further promote mitophagy initiation. Autophagosome–lysosome fusion: Recognized mitochondria are ultimately degraded via autophagosome maturation and lysosomal fusion.

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  FIGURE 3. Dual‐threshold model of mitophagy failure and inflammatory amplification in cardiovascular diseases. Under homeostatic conditions, MQC and mitophagy restrict the accumulation of mitochondria‐derived DAMPs and maintain inflammatory activation below threshold. When MQC capacity declines, damaged mitochondria accumulate and release mtDNA, mtROS, and oxidized mitochondrial components, thereby activating PRR‐related signaling, inflammasomes, and the cGAS–STING pathway. The resulting inflammatory cytokine production further disrupts mitochondrial homeostasis, suppresses PGC‐1α/SIRT3/TFAM‐associated MQC, reduces mitophagy efficiency, and lowers the inflammatory activation threshold. This bidirectional feedback establishes a self‐sustaining inflammatory amplification circuit driven by dual‐threshold disequilibrium.

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  FIGURE 4. Stage‐, cell‐, and threshold‐dependent framework of inflammatory heterogeneity in cardiovascular diseases. Inflammatory responses in CVDs are jointly shaped by temporal dynamics, cell type‐specific organization, and intensity‐dependent threshold gating. Representative disease settings can be mapped into three major patterns: Acute high‐intensity inflammation in myocardial infarction/myocardial ischemia–reperfusion injury, chronic low‐grade inflammatory persistence in atherosclerosis and diabetic cardiomyopathy, and maladaptive inflammatory maintenance and remodeling in pressure overload, cardiotoxicity, and related cardiomyopathic conditions. Mitochondrial integrity, mitophagy, redox balance, and metabolic state function as key gating mechanisms that determine whether inflammation supports adaptive repair or progresses to pathological remodeling.

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  FIGURE 5. Network‐guided therapeutic framework and translational roadmap for cardiovascular inflammation. Therapeutic intervention in cardiovascular inflammation can be stratified across multiple network layers, including upstream danger signal control through MQC, intermediate suppression of inflammatory priming, inflammasome amplification, and nucleic acid sensing, and higher order restoration of immunometabolic gating. The translational pathway further requires biomarker‐based patient selection, stage‐informed trial prototypes, integrated efficacy assessment, and mechanism‐informed safety monitoring. This framework highlights that effective therapy should focus on layered and context‐dependent regulation of inflammatory networks rather than indiscriminate inhibition of single pathways.