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PD-1 inhibition disrupts collagen homeostasis and aggravates cardiac dysfunction through endothelial-fibroblast
Zejin Zhang1,2, Zhenzhen Yan2,3, Tao Yuan2,4
1School of Pharmacy, Binzhou Medical University, Yantai, Shandong, China.
Insights
PD-1 inhibitors cause cardiac collagen remodeling by affecting endothelial cells and fibroblasts, leading to heart dysfunction. N-acetylcysteine (NAC) may prevent these immune-related adverse events by restoring normal collagen distribution and cardiac function.
Area of Science:
- Cardiology
- Immunology
- Cell Biology
Background:
- Immune checkpoint inhibitors (ICIs) targeting PD-1 can cause cardiac immune-related adverse events (irAEs) with high mortality.
- The impact of PD-1 inhibitors on cardiac collagen remodeling and its underlying mechanisms are not well understood.
Purpose of the Study:
- To investigate the cardiotoxic effects of PD-1 inhibitors on cardiac collagen remodeling.
- To elucidate the mechanisms by which PD-1 inhibitors induce cardiac dysfunction, focusing on endothelial-cardiac fibroblast crosstalk and collagen deposition.
Main Methods:
- Utilized a mouse model of PD-1 inhibitor treatment.
- Assessed cardiac function via echocardiography and analyzed collagen distribution using histological staining.
- Employed single-nucleus RNA sequencing, co-culture experiments, ELISA, ChIP assays, Western blot, qRT-PCR, immunofluorescence, and ROS level assays.
Main Results:
- PD-1 inhibitor treatment led to aberrant cardiac collagen distribution, decreasing interstitial collagen and increasing perivascular collagen.
- The mechanism involves PD-1 inhibitor-induced reactive oxygen species (ROS) accumulation in cardiac endothelial cells (ECs), leading to downregulated TCF12 and reduced TGF-β1 secretion.
- This disrupts EC-cardiac fibroblast (CF) crosstalk, impairs CF activity, and promotes endothelial-to-mesenchymal transition (EndMT), contributing to collagen imbalance and cardiac dysfunction.
- N-acetylcysteine (NAC) administration reversed these effects, preserving collagen distribution and cardiac function.
Conclusions:
- PD-1 inhibitors induce cardiac dysfunction through ROS-mediated disruption of collagen distribution via TCF12/TGF-β1 signaling and EndMT.
- NAC supplementation shows potential as a clinical strategy to mitigate PD-1 inhibitor-induced cardiotoxicity.
Introduction:
Cardiac immune-related adverse events (irAEs) from PD-1-targeting immune check-point inhibitors (ICIs) are an increasing concern due to their high mortality rate. Collagen plays a crucial role in maintaining cardiac structure, elasticity, and signal transduction; however, the effects and mechanisms of PD-1 inhibitor on cardiac collagen remodeling remain poorly understood.
Methods:
C57BL/6 mice were injected with anti-mouse PD-1 antibody to create a PD-1 inhibitor-treated model. Cardiac function was measured by echocardiography, and collagen distribution was analyzed with Masson's trichrome staining and Sirius Red staining. Single-nucleus RNA sequencing was performed to examine the effects of PD-1 inhibition on gene expression in cardiac fibroblasts (CFs) and endothelial cells (ECs). EC-CF crosstalk was assessed using co-culture experiments and ELISA. ChIP assay was performed to analyze the regulation of TCF12 on TGF-β1 promoter. Western blot, qRT-PCR, and immunofluorescence staining were used to detect the expression of TCF12, TGF-β1, and endothelial-to-mesenchymal transition (EndMT) markers. Reactive oxygen species (ROS) levels were evaluated by DHE staining, MDA content, and SOD activity assays.
Results:
We report a newly discovered cardiotoxic effect of PD-1 inhibitor, which causes aberrant collagen distribution in the heart, marked by a decrease in interstitial collagen and an increase in perivascular collagen deposition. Mechanistically, PD-1 inhibitor does not directly affect CFs but instead impact them through EC-CF crosstalk. PD-1 inhibitor reduces TGF-β1 secretion in ECs by downregulating TCF12, which we identify as a transcriptional promoter of TGF-β1. This subsequently decreases CF activity, leading to reduced interstitial collagen deposition. Additionally, PD-1 inhibitor induces EndMT, increasing perivascular collagen deposition. The endothelial dysfunction induced by PD-1 inhibitor results from ROS accumulation in ECs. Inhibiting ROS with N-acetylcysteine (NAC) preserves normal collagen distribution and cardiac function in PD-1 inhibitor-treated mice by reversing TCF12 downregulation and EndMT in ECs.
Conclusion:
Our results suggest that PD-1 inhibitor causes ROS accumulation in cardiac ECs, leading to imbalanced collagen distribution (decrease in interstitial collagen and increase in perivascular collagen) in the heart by modulating TCF12/TGF-β1-mediated EC-CF crosstalk and EndMT. NAC supplementation could be an effective clinical strategy to mitigate PD-1 inhibitor-induced imbalanced collagen distribution and cardiac dysfunction.
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