CD38 Links Heart and Brain Disease Through Shared Molecular Pathways
A comprehensive review reveals how the enzyme CD38 drives cardiovascular and neurological disease through calcium, NAD+, and inflammation signaling.
Summary
CD38 is a multifunctional transmembrane enzyme expressed in the heart, brain, and immune cells. This review synthesizes evidence showing CD38 drives myocardial ischemia-reperfusion injury, heart failure, atherosclerosis, and arrhythmias, while simultaneously contributing to neuroinflammation, Alzheimer's disease, depression, and stroke. The enzyme exerts its damage through four overlapping mechanisms: intracellular calcium dysregulation, NAD+ depletion, oxidative stress, and inflammatory immune activation. Crucially, CD38 inhibitors—including luteolinidin, compound 78c, MK-0159, and the clinical antibody daratumumab—show protective effects across both organ systems. The authors argue CD38 represents a uniquely positioned therapeutic target for the growing population of patients suffering from concurrent heart-brain disorders.
Detailed Summary
Heart disease and brain disease frequently co-occur, yet shared molecular mechanisms underlying this comorbidity remain poorly characterized. This review from researchers at Soochow University and Nanjing Medical University synthesizes the rapidly evolving literature on CD38—a 45 kDa transmembrane glycoprotein originally identified as a lymphocyte differentiation antigen—and its dual role in cardiovascular and neurological pathology.
CD38 functions as both a NADase and a cyclase, hydrolyzing NAD+ and generating second messengers including cyclic ADP-ribose (cADPR), ADPR, and NAADP. These products mobilize intracellular calcium from the sarcoplasmic reticulum and lysosomes, regulate redox balance, and modulate immune cell function. While historically studied in hematological cancers and immune biology, CD38 is now recognized as highly expressed in cardiac endothelial cells, cardiomyocytes, vascular smooth muscle, neurons, astrocytes, and microglia.
In the cardiovascular system, CD38 overactivation during myocardial ischemia-reperfusion injury depletes NADP(H), promotes calcium overload, and generates excess reactive oxygen species (ROS). CD38 deficiency or pharmacological inhibition activates protective SIRT1/FOXOs and Sirt3/FOXO3 antioxidant pathways, reduces infarct size, and preserves cardiac contractility. In atherosclerosis, CD38 regulates macrophage lysosomal cholesterol handling via the NAADP pathway, and its loss disrupts autophagic flux and activates the NLRP3 inflammasome, accelerating coronary arterial wall thickening. In heart failure, CD38 promotes cardiac hypertrophy and fibrosis through Ca²⁺-NFAT signaling and SIRT3 inhibition. In arrhythmia models, CD38-driven calcium dysregulation activates CaMKII and TRPM2 channels, predisposing to atrial fibrillation.
In the brain, CD38 is implicated in neuroinflammation by activating microglia and astrocytes, elevating pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), and depleting NAD+—a cofactor critical for neuronal energy metabolism and sirtuin-dependent neuroprotection. In Alzheimer's disease models, CD38 activity correlates with amyloid-beta accumulation and tau hyperphosphorylation, partly through NAD+ reduction impairing SIRT1-mediated clearance mechanisms. In stroke and cerebral ischemia, CD38 exacerbates neuronal death via calcium excitotoxicity and oxidative damage. In depression and psychiatric disorders, CD38 influences oxytocin signaling in the hypothalamus, with polymorphisms in the CD38 gene associated with social behavior deficits and mood dysregulation.
Several CD38 inhibitors are highlighted as promising: luteolinidin, the thiazoloquinazolinone compound 78c, the orally bioavailable MK-0159, and the FDA-approved anti-CD38 monoclonal antibody daratumumab. These agents show efficacy across both cardiac and neural injury models, supporting the concept of CD38 as a heart-brain axis therapeutic target. The authors call for large randomized clinical trials and more mechanistic studies—particularly in HFpEF and combined heart-brain disease populations—to determine the safety and efficacy of CD38-targeted interventions in humans.
Key Findings
- CD38 drives myocardial I/R injury via NADP(H) depletion, calcium overload, and ROS; its inhibition activates SIRT1/SIRT3 antioxidant pathways.
- CD38 loss disrupts macrophage lysosomal cholesterol efflux and autophagic flux, accelerating coronary atherosclerosis via NLRP3 inflammasome activation.
- In the brain, CD38 contributes to Alzheimer's disease, neuroinflammation, stroke, and depression through NAD+ depletion and calcium dysregulation.
- CD38 inhibitors (luteolinidin, 78c, MK-0159, daratumumab) show protective effects across both cardiac and neurological disease models.
- CD38 gene polymorphisms are linked to altered oxytocin signaling, social behavior deficits, and psychiatric vulnerability.
Methodology
This is a narrative review synthesizing preclinical animal studies (CD38 knockout mice, pharmacological inhibitor models), clinical observations (case reports, bioinformatics analyses), and mechanistic cell biology data. No original experimental data were generated; conclusions are drawn from aggregated published literature across cardiovascular and neuroscience fields.
Study Limitations
As a narrative review, it is subject to selection bias and does not include meta-analytic quantification of effect sizes. Most mechanistic evidence derives from rodent knockout and pharmacological models, limiting direct translation to human disease. Large randomized clinical trials specifically targeting CD38 in cardiovascular or neurological disorders have not yet been conducted.
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