Exercise in ozone-polluted air evokes pathological cardiac hypertrophy via up-regulation of nuclear lncRNA EYA4-au1 and recruiting Med11 to activating EYA4/p27kip1/CK2α/HDAC2 cascade.

Engaging in exercise in an ozone (O3)-polluted environment can lead to lung damage, respiratory inflammation, and deterioration in performance, however, the effects on the heart are undefined. Herein, we report that rats performing moderate-intensity exercise under O3-polluted air evoked pathological myocardial hypertrophy (MH). O3 exposure increased serum levels of MH-promoting factors (angiotensin II [AngII], endothelin-1 [ET-1], and cyclophilin A [CyPA]), and decreased expression of MH-inhibiting factors (adiponectin [ADPN], follistatin-like protein 1 [FSTL1], and apelin). O3 exposure also increased the expression levels of cardiac hypertrophy markers (ANP, BNP, and β-MHC) in the heart, elicited myocardial hypertrophy and cardiac inflammation. Mechanistically, we identified lncRNA EYA4-au1 overexpression in the above myocardial tissues with pathological hypertrophy. In an AngII-elicited in vitro model, EYA4-au1 was shown to mediate cardiomyocyte hypertrophy. AngII induces nuclear translocation of SP1, leading to high expression of EYA4-au1; And inhibits the expression of ELAVL1, resulting in nuclear retention of EYA4-au1. Nuclear EYA4-au1 recruits Med11 to EYA4 promoter for transcriptional activation, subsequently unleashing the EYA4/p27kip1/CK2α/HDAC2 cascade that signals cardiomyocyte hypertrophy. In summary, O3 exposure is an important factor in pathological MH, mediated by EYA4-au1 that motivates the MH-driving EYA4 pathway. Our findings define the effects of exercise on the heart in an O3-polluted environment and offer a novel mechanistic route for the onset of MH.