Macrophage NLRP3-dependent IL-1β production contributes to aortic fibrosis in heart failure with preserved ejection fraction.

Fibrosis is the main pathological feature of aortic stiffness, which is a common extracardiac comorbidity of heart failure with preserved ejection fraction (HFpEF) and a contributor to left ventricular (LV) diastolic dysfunction. Systemic low-grade inflammation plays a crucial role in the pathogenesis of HFpEF and the development of vascular fibrosis. In this study, we investigate the inflammatory mechanism of aortic fibrosis in HFpEF using a novel mouse model. LV diastolic dysfunction with preserved ejection fraction and aortic fibrosis induced by a high-fat diet (HFD) combined with subcutaneous aldosterone infusion are utilized. The constructed model exhibits augmented macrophage recruitment and NLR family pyrin domain containing 3 (NLRP3)-dependent interleukin (IL)-1β production in fibrotic aortas. In addition, a bone marrow transplant is employed to induce macrophage-specific NLRP3 deficiency in the HFpEF mouse model. These mice show almost completely suppressed cleaved-caspase-1 and mature IL-1β protein expression in the aortas, indicating that macrophage NLRP3 inflammasome activation enhances the IL-1β overproduction in fibrotic aortas. Furthermore, we show that macrophage NLRP3 inflammasome inhibition improves aortic fibrosis and LV diastolic dysfunction. In conclusion, this study demonstrates the pivotal effect of macrophage NLRP3-dependent IL-1β production on aortic fibrosis and cardiac function in HFpEF, suggesting a potential target for HFpEF therapy.