Pharmacological inhibition of the interleukin-1 receptor-associated kinase prevents angiotensin II-induced cardiac remodelling in mice.

BACKGROUND AND PURPOSE: Angiotensin II (AngII) induces cardiac hypertrophy but the exact mechanism is not known. The present study investigates the role of the interleukin-1 receptor-associated kinase (IRAK), in AngII-induced cardiac inflammation, fibrosis and hypertrophy.

EXPERIMENTAL APPROACH: C57BL/6J male mice were infused with saline (sham) or AngII (1.5 mg·kg-1·day-1, subcutaneously) along with vehicle or IRAK-1/4 inhibitor (2.21 mg·kg-1, intra-peritoneal) for 4 weeks. Cardiac hypertrophy, fibrosis and signalling mechanisms were examined by echocardiography, histopathology, immunohistochemistry, RT-qPCR and immunoblotting, respectively, in the left ventricle (LV). H9C2 cells and primary cardiac fibroblasts were used to complement the in vivo studies.

KEY

RESULTS

AngII infusion in mice leads to significant alterations in haemodynamic and gravimetric parameters and the development of cardiac hypertrophy, inflammation and fibrosis in comparison with sham mice. Treatment with IRAK-1/4 inhibitor prevented the AngII-induced changes in ejection fraction, fractional shortening, systolic blood pressure and relative heart weight, compared with mice given AngII alone. AngII-induced increase in cardiomyocyte cross-sectional area and fetal genes (Acta1, Mhy6, Nppa) expression were also attenuated in IRAK-1/4 inhibitor-treated mice. CD45, F4/80, CD68 and CD3 immuno-staining showed reduced immune cell infiltration in IRAK-1/4 inhibitor and AngII-infused mice when compared with AngII alone. IRAK-1/4 inhibitor and siRNA prevented AngII-induced H9C2 cell hypertrophy and activation of fibroblast TGFβ-SMAD pathway, respectively. Mechanistically IRAK-1/4 inhibitor prevents activation of Ang II-induced TLR4-NF-κB and TGFβ-SMAD pathway.

CONCLUSION AND IMPLICATIONS: The IRAK-1/4 inhibitor reduced cardiac inflammation, fibrosis and hypertrophy through the TLR4-NF-κB and TGFβ-SMAD pathways, suggesting therapeutic potential for cardio-inflammatory heart failure.