GRK2-facilitated TLR4 signaling promotes cardiac fibrosis in rheumatic mice

Patients with rheumatoid arthritis (RA) have a much higher prevalence of cardiac dysfunction, which explains the high mortality rate in RA patients despite treatment with anti-arthritic drugs. This study elucidates a molecular mechanism that causes abnormal activation of cardiac fibroblasts in the inflammatory state of RA through transactivation of canonical TLR4 signaling by GRK2-dependent signaling mechanisms, and which ultimately induces heart disease.

Collagen-induced arthritis (CIA) models were established in mice, and the cardiac function in these CIA mice was dynamically examined using echocardiography. Cardiac diastolic and systolic dysfunction appeared and persisted in the hearts of CIA mice even after joint inflammation subsides, and significant fibrosis occurred in the cardiac tissue. TLR4 expression was elevated in the hearts of CIA mice which was associated with cardiac fibrosis. Cardiac fibroblasts from CIA mice undergo aberrant proliferation and a significant increase in NF-κB p65 nuclear translocation. Treatment with the specific TLR4 inhibitor, TAK-242, effectively protected CIA mice from cardiac fibrosis and cardiac diastolic dysfunction. Cardiac function was effectively rescued by administration of the GRK2 inhibitor paroxetine and carvedilol as well, with a concomitant reduction in NF-κB nuclear localization. In cardiac tissues of CIA mice, elevated levels of GRK2 expression thereby cause cardiac fibroblasts to undergo transdifferentiation.

GRK2 transactivates TLR4 signaling, which promoted cardiac fibroblast transdifferentiation. Furthermore, GRK2 inhibition effectively mitigated myocardial fibrosis and protected cardiac function, which offered an important strategy to protect RA patients from heart failure.