.png){kind=icon}
.png){kind=icon}
Return
A platelet-monocyte pyroptotic axis mediates uremic cardiomyopathy: critical role of PF4 and hematopoietic caspase-1
.png){kind=icon}
PRE
AI
Y
M
M
X
J
T
D
D
L
A
C
DOI：10.1007/s00011-026-02311-9.png)
.png){kind=icon}
Original request for help.png){kind=icon}
Share.png){kind=icon}
Save
Abstract
En 中文
Cardiovascular disease is the leading cause of death in end-stage renal disease (ESRD). While platelet activation and monocyte inflammation are hallmarks of uremia, how platelet-derived factors drive monocyte-mediated cardiac remodeling remains elusive. We investigated the role of platelet factor-4 (PF4) in monocyte pyroptosis and its contribution to uremic cardiomyopathy. A uremic mouse model was established by 5/6 nephrectomy (Nx). Differentially expressed genes between Ly6C⁺ and Ly6C⁻ monocyte subsets were identified by microarray and WGCNA. PF4 effects were assessed by systemic administration with or without CXCR3 inhibition or PF4 neutralization. Caspase-1 activation was evaluated by FAM-FLICA staining and IL-1β ELISA. The role of caspase-1 was examined using global Casp1⁻/⁻ mice and bone marrow (BM) transfer experiments. In uremic mice, circulating Ly6C⁺ monocytes decreased time-dependently. Bioinformatics identified Pf4 as a key hub gene, with six pyroptosis-associated genes upregulated in Ly6C⁺ monocytes versus sham controls. PF4 infusion, at least in part through CXCR3, shortened Ly6C⁺ monocyte lifespan, upregulated pyroptosis-related genes, increased active caspase-1⁺ cells and IL-1β release, and accelerated cardiac dysfunction and fibrosis. CXCR3 inhibition or PF4 neutralization attenuated these effects. Global Casp1 knockout, which retained intact Casp11 expression, protected mice from PF4-exacerbated cardiac injury. BM transplantation from Casp1⁻/⁻ into wild-type mice conferred the same protective phenotype, identifying BM-derived caspase-1 as a key driver. Our study identifies a pathway where PF4, acting partly through CXCR3, contributes to caspase-1-dependent pyroptosis in Ly6C⁺ monocytes, driving pathological cardiac remodeling in uremia. Targeting this axis in BM-derived cells may represent a therapeutic strategy for heart failure in ESRD.
Keywords:
Heart failure
End-stage renal disease
Monocyte
Caspase
Pyroptosis
Journal
IF:
5.4
Papers:
3.3K
Citations:
7.2K
Organization
Cited Papers