Activating PPARα in macrophages attenuates arterial remodeling via inhibiting YAP nuclear localization

Arterial remodeling is strongly linked to cardiovascular morbidity and mortality. Adventitial inflammation is a key driver in the pathological process of arterial remodeling. However, the underlying molecular mechanism remains largely unknown. This study was conducted to elucidate the role and mechanism of peroxisome proliferator-activated receptor alpha (PPARα) in arterial remodeling. Here, by using the transverse aortic constriction (TAC) model to mimic overload pressure-induced arterial remodeling, we observed significantly decreased expression of PPARα in macrophages that infiltrated into the remodeled arterial adventitia, whereas the administration of PPARα agonist Wy14643 efficiently ameliorated such arterial changes, especially in adventitia. PPARα activation strengthened its interaction with yes-associated protein (YAP) in the cytoplasm thus decreasing the translocation of YAP into nucleus to trigger macrophage infiltration and polarization toward the classical activation phenotype. Finally, blockade of YAP signaling could also suppress pathological arterial alternations in the TAC model. Our study thus identifies PPARα as a promising therapeutic target for treating arterial remodeling.