Periostin-CCL3 Feedforward Signaling Loop Promotes Cardiac Fibrosis and Cardiomyocyte Necroptosis in Arrhythmogenic Cardiomyopathy.

Periostin (POSTN) is a multifunctional extracellular matrix protein in cardiovascular diseases. However, its role in arrhythmogenic cardiomyopathy (ACM) remains unknown. Here, we demonstrate that POSTN is significantly elevated in the myocardium of ACM mice and patients. POSTN deficiency alleviates heart dysfunction, reduces cardiac fibrosis and improves survival rates in ACM mice. POSTN is mainly derived from cardiac myofibroblasts and promotes cardiomyocyte necroptosis in vivo and in vitro. Mechanistically, POSTN facilitates cardiomyocyte necroptosis through the integrin-JNK-RIP3-MLKL signaling and induces CCL3 expression via the integrin-JNK-ETS2 pathway. In turn, CCL3 activates cardiac myofibroblasts and stimulates POSTN expression through the NF-κB signaling. Our findings show that POSTN and CCL3 facilitate ACM progression through the POSTN-integrin-JNK-ETS2-CCL3 signaling in cardiomyocytes and CCL3-CCR5-NF-κB-POSTN axis in cardiac myofibroblasts. We further found that pharmacological inhibition of either JNK or CCR5 to target JNK-CCL3-CCR5 axis attenuates subsequent ACM progression in mice by suppressing cardiac fibrosis and cardiomyocyte necroptosis. Therefore, targeting the POSTN-CCL3 feedforward signaling loop may offer a novel therapeutic strategy for patients with ACM.