LTBP4 deficiency inhibits NLRP3 inflammasome activation in cardiomyocytes and attenuates heart failure in male mice.

Summary

This mechanistic study shows that LTBP4 is upregulated in human and murine heart failure and that cardiomyocyte-specific Ltbp4 deficiency limits NLRP3 inflammasome activation, reduces fibrosis, and improves function after pressure overload. LTBP4 facilitates dynein-dependent NLRP3 trafficking to the MTOC and strengthens NLRP3–NEK7 interactions, with SP1-driven transcriptional upregulation under pressure overload.

Key Findings

• LTBP4 expression is increased in plasma and cardiomyocytes of HF patients and in TAC-induced HF in male mice.
• Cardiomyocyte-specific Ltbp4 deficiency reduces NLRP3 inflammasome activation, fibrosis, and ventricular dysfunction after TAC.
• Pressure overload upregulates LTBP4 via SP1; intracellular LTBP4 assists dynein-mediated NLRP3 trafficking to the MTOC and promotes NLRP3–NEK7 interaction, also enhancing NLRP3 transcription.

Clinical Implications

Targeting LTBP4 or its trafficking pathway could offer a new anti-inflammatory strategy for heart failure by dampening NLRP3 inflammasome activation upstream of IL-1β signaling.

Limitations

• Predominantly male murine model; sex-specific effects remain undefined.
• No pharmacologic inhibition or genetic rescue of LTBP4 tested in large-animal models; translational path needs validation.

Future Directions

Develop and test pharmacologic or genetic modulators of LTBP4–dynein–NLRP3 trafficking in large-animal models and assess sex-specific efficacy and safety.