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Global Translational Medicine Anti-inflammatory therapy in CVD

IL-36, offer new insights into vascular inflammation. potential risks, such as unintended immunosuppression
IL-17F amplifies inflammatory cytokine and chemokine and thrombosis. Dual targeting of CD47 and vascular
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production, promoting neutrophil recruitment and endothelial growth factor has been explored to enhance
endothelial dysfunction. IL-33, released upon cellular the resolution of inflammation while preventing excessive
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injury, interacts with the ST2 receptor to activate myeloid angiogenesis within unstable plaques.
differentiation primary response protein 88 and NF-κB, Serum/glucocorticoid-regulated kinase 1 (SGK1),
triggering pro-inflammatory cascades that drive immune a kinase that regulates sodium retention, fibrosis, and
cell recruitment. IL-34 binds to macrophage colony- cellular survival, is pivotal in cardiovascular remodeling
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stimulating factor 1 receptor, sustaining monocyte and and arrhythmogenesis. Upregulation of SGK1 has
macrophage survival in inflamed tissues and exacerbating been implicated in myocardial hypertrophy, ischemia-
vascular pathology. IL-36, a member of the IL-1 family, reperfusion injury, and ion channel dysfunction.
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is activated by neutrophil-derived enzymes, amplifying Pharmacologic inhibition of SGK1 with small-molecule
immune cell adhesion and endothelial dysfunction, inhibitors, such as GSK650394 and EMD638683, has
perpetuating chronic inflammation in vascular tissues. 35
shown promise in mitigating hypertrophic signaling and
Advancements in monoclonal antibody therapies have reducing cardiac fibrosis. In addition to its role in cardiac
provided targeted approaches to modulating vascular remodeling, SGK1 inhibition has been explored as a
inflammation. In the CANTOS trial, canakinumab, an potential strategy to modulate arrhythmogenic substrates
IL-1β inhibitor, demonstrated a 15% reduction in major by influencing NaV and K channel activity, reducing the
+
1.5
cardiovascular events, validating IL-1β as a therapeutic likelihood of prolonged action potentials and arrhythmias.
target in atherosclerosis. Tocilizumab, an IL-6 receptor Moreover, SGK1 inhibition may provide cardioprotective
antagonist, improved myocardial salvage and significantly effects against oxidative stress, particularly in conditions
reduced inflammatory markers in the Assessing the such as doxorubicin-induced cardiomyopathy.
Effect of Anti-IL-6 Treatment in Myocardial Infarction
(ASSAIL-MI) trial, suggesting a role in acute coronary P-selectin, an adhesion molecule stored in platelet
syndromes. 35,36 Secukinumab, targeting IL-17A, and α-granules and endothelial Weibel–Palade bodies, is a key
ustekinumab, inhibiting IL-12/23, have demonstrated driver of thromboinflammation. P-selectin contributes
robust anti-inflammatory effects in autoimmune diseases to platelet aggregation, endothelial dysfunction, and
and may provide cardiovascular benefits by reducing vascular inflammation by mediating leukocyte rolling and
systemic inflammation. 37,38 Bimekizumab, which inhibits adhesion. Pharmacologic strategies targeting P-selectin
both IL-17A and IL-17F, showed a 91% reduction in the include monoclonal antibodies, glycomimetic inhibitors,
Psoriasis Area and Severity Index response rate in the BE and small-molecule antagonists. 44 Crizanlizumab,
READY trial, underscoring its potent anti-inflammatory a monoclonal antibody targeting P-selectin, has
properties. Spesolimab, an IL-36 receptor antagonist, and demonstrated clinical efficacy in reducing vaso-occlusive
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astegolimab targeting IL-33/ST2 offer promising strategies to episodes in sickle cell disease and is now being investigated
reduce endothelial activation and immune-driven vascular for cardiovascular applications to mitigate thrombosis-
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injury. 40,41 related complications. In addition, PSI-697, an orally
available P-selectin inhibitor, has shown potential in
9. Emerging therapeutic targets in CVD reducing atherogenesis and vascular injury in preclinical
models. 44
Cluster of differentiation 47 (CD47), a transmembrane
glycoprotein known as the “don’t eat me” signal, prevents the Growth/differentiation factor 15 (GDF-15), a member
clearance of apoptotic and damaged cells by macrophages, of the transforming growth factor-beta superfamily, has
leading to persistent inflammation in atherosclerotic gained attention both as a biomarker and a therapeutic target
plaques. Inhibition of CD47-signal regulatory protein- in CVD. Elevated GDF-15 levels correlate with adverse
alpha (SIRPα) signaling enhances macrophage-mediated outcomes in heart failure, myocardial infarction, and atrial
efferocytosis, reducing necrotic core size, inflammation fibrillation, reflecting its role in cellular stress responses
levels, and plaque burden. Experimental studies have and inflammation. Therapeutically, modulation of GDF-
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shown that CD47 blockade with monoclonal antibodies 15 signaling has been explored to mitigate maladaptive
or SIRPα-Fc fusion proteins facilitates the clearance of inflammatory responses and vascular dysfunction. GDF-
apoptotic debris while improving endothelial function and 15 influences leukocyte integrin activation and endothelial
neovascularization. However, since CD47 inhibition also function, suggesting that targeting its signaling axis could
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plays a role in immune surveillance, careful consideration provide cardioprotective effects, particularly in conditions
is required to balance its cardiovascular benefits with characterized by excessive vascular inflammation and

Volume 4 Issue 3 (2025) 18 doi: 10.36922/GTM025100024