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

• Published in: Ecotoxicology and environmental safety 2024-11, Vol.287, p.117264, Article 117264
• Main Authors: Zhao, Jiao, Gong, Fuxu, Yang, Qingcheng, Yang, Renxin, Yan, Zhangong, Xi, Zhuge, Li, Kang, Lai, Wenqing, Shi, Yue, Lin, Bencheng, Yan, Jun, Liu, Xiaohua
• Format: Article
• Language: English
• Subjects: Air Pollutants - toxicity; Air Pollution - adverse effects; Animals; Cardiac hypertrophy; Cardiomegaly - chemically induced; Cardiomegaly - genetics; Exercise; EYA4-au1; Male; Med11; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Ozone; Ozone - toxicity; Rats; Rats, Sprague-Dawley; RNA, Long Noncoding - genetics; Up-Regulation
• ISSN: 0147-6513; 1090-2414; 1090-2414
• DOI: 10.1016/j.ecoenv.2024.117264

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. [Display omitted] •Exercise in ozone-polluted air elicited myocardial hypertrophy and cardiac inflammationinduced in rats.•Regular exercise can partially reverse intermittent ozone induced myocardial hypertrophy.•lncRNA EYA4-au1 is a novel lncRNA that promotes myocardial hypertrophy.•SP1 and ELAVL1 can induce EYA4-au1 nuclear retention.•EYA4-au1 activates the p27kip1/CK2 α/HDAC2 axis by acting on neighboring gene EYA4.