JAHA.2021.pdf

BACKGROUND: Hypertension-induced

cardiovascular remodeling is characterized by chronic low-grade

inflammation.

Interleukin-4

receptor α (IL-4Rα)

signaling is importantly involved in cardiovascular remodeling, however, the target cell type(s)

is unclear. Here, we investigated the role of myeloid-specific

IL-4Rα

signaling in cardiovascular remodeling induced by angiotensin

II and high salt.

METHODS AND RESULTS: Myeloid IL-4Rα

deficiency suppressed both the in vitro and in vivo expression of alternatively activated

macrophage markers including Arg1 (arginase 1), Ym1 (chitinase 3-like

3), and Relmα/Fizz1 (resistin-like

molecule α). After

angiotensin II and high salt treatment, myeloid-specific

IL-4Rα

deficiency did not change hypertrophic remodeling within the

heart and aorta. However, myeloid IL-4Rα

deficiency resulted in a substantial reduction in fibrosis through the suppression

of profibrotic pathways and the enhancement of antifibrotic signaling. Decreased fibrosis was associated with significant

preservation of myocardial function in MyIL4RαKO mice and was mediated by attenuated alternative macrophage activation.

CONCLUSIONS: Myeloid IL-4Rα

signaling is substantially involved in fibrotic cardiovascular remodeling by controlling alternative

macrophage activation and regulating fibrosis-related

signaling. Inhibiting myeloid IL-4Rα

signaling may be a potential strategy

to prevent hypertensive cardiovascular diseases.