Macrophage-Specific SPP1 Contributes to Pressure Overload-Induced Cardiac Dysfunction and Maladaptive Remodeling

Area of Science:

• Cardiovascular Biology
• Immunology
• Molecular Medicine

Background:

• Cardiac macrophages are key in myocardial remodeling but pathogenic subsets are unclear.
• Understanding these subsets is crucial for treating heart disease.

Purpose of the Study:

• Identify pathogenic macrophage subsets in pressure overload.
• Elucidate the regulatory mechanisms driving cardiac pathogenesis.
• Evaluate therapeutic targeting of identified pathways.

Main Methods:

• Utilized transverse aortic constriction model in mice.
• Investigated macrophage subpopulations and their secreted proteins.
• Employed genetic deletion (Spp1) and pharmacological inhibition (arglabin).

Main Results:

• Identified an early-emerging SPP1-expressing pathogenic macrophage subset.
• Myeloid Spp1 deletion attenuated cardiac inflammation and dysfunction.
• Discovered the HMGB1-NLRP3-NF-κB-SPP1 axis driving pathogenesis.
• Arglabin inhibited this axis, reducing fibrosis and improving remodeling.

Conclusions:

• A critical HMGB1-NLRP3-NF-κB-SPP1 axis in macrophages drives pressure overload-induced cardiac pathogenesis.
• Targeting this axis, e.g., with arglabin, is a promising therapeutic strategy for pathological cardiac remodeling.