Key result
NLRP3 inhibition or GLP-1RA rescues macrophage-driven cardiomyocyte dysfunction in preclinical HFpEF.
Why the study?
The cellular mechanisms linking immune activation and myocardial inflammation to cardiomyocyte injury in HFpEF remained incompletely understood, prompting investigation into whether macrophage-driven NLRP3 inflammasome activation mediates cardiomyocyte dysfunction.
Does inhibition of macrophage-driven NLRP3 inflammasome activation (via MCC950, siRNA knockdown, or GLP-1 receptor agonist) reduce inflammatory responses and improve cardiomyocyte function in models of HFpEF?
Does inhibition of macrophage-driven NLRP3 inflammasome activation (via MCC950, siRNA knockdown, or GLP-1 receptor agonist) reduce inflammatory responses and improve cardiomyocyte function in models of HFpEF?
Macrophage-driven NLRP3 inflammasome activation promotes cardiomyocyte dysfunction in HFpEF via NF-κB signaling, which can be mitigated in vitro by MCC950, NLRP3 siRNA knockdown, or GLP-1 receptor agonist treatment.
Supports NLRP3 targeting in HFpEF models; leaves open clinical translation of MCC950 or GLP-1 agonists.
Background Heart failure with preserved ejection fraction (HFpEF) is characterized by diastolic dysfunction and myocardial inflammation, but the cellular mechanisms linking immune activation to cardiomyocyte injury remain incompletely understood. We investigated whether macrophage-driven NLRP3 inflammasome activation mediates cardiomyocyte dysfunction in HFpEF. Methods Cardiac macrophage infiltration, NLRP3 inflammasome activation, and NF-κB nuclear translocation were assessed in HFpEF mouse hearts and human heart specimens by immunostaining, ELISA and Western blot. Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were exposed to conditioned media from macrophages to evaluate NF-κB activation, mitochondrial function, and calcium handling. Pharmacological inhibition (MCC950), siRNA knockdown (NLRP3), and GLP-1 receptor agonist treatment were applied in vitro to assess rescue effects. Results HFpEF hearts exhibited increased macrophage accumulation accompanied by enhanced NLRP3 inflammasome activation, as evidenced by elevated caspase-1 cleavage and mature IL-1β production. This was associated with increased NF-κB nuclear translocation in cardiomyocytes. In iPSC-CMs, macrophage-conditioned media induced robust NF-κB activation, mitochondrial fragmentation, oxidative stress, and impaired calcium transient. Pharmacological inhibition of NLRP3 with MCC950 or siRNA-mediated knockdown significantly reduced inflammatory responses. GLP-1 receptor agonist treatment also suppressed NLRP3 activation and IL-1β production, mitigating macrophage-driven inflammation. Conclusions Macrophage-driven NLRP3 inflammasome activation in HFpEF promotes NF-κB nuclear translocation in cardiomyocytes, contributing to functional impairment. Functional rescue by GLP-1RA, MCC950, or siRNA in iPSC-CMs highlights potential therapeutic avenues in vitro. These findings provide mechanistic insight into HFpEF-associated myocardial inflammation and suggest macrophage inflammasome signaling as a targetable axis.
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Dong et al. (2026) studied Heart failure with preserved ejection fraction (HFpEF). MCC950, NLRP3 siRNA knockdown, and GLP-1 receptor agonist vs. Untreated macrophage-conditioned media / control was evaluated on NLRP3 inflammasome activation, NF-κB nuclear translocation, mitochondrial function, and calcium handling. Macrophage-driven NLRP3 inflammasome activation promoted cardiomyocyte NF-κB activation and dysfunction in HFpEF, which was rescued in vitro by MCC950, NLRP3 siRNA, or GLP-1RA.
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