Mitochondria damage in ambient particulate matter induced cardiotoxicity: Roles of PPAR alpha/PGC-1 alpha signaling

Qixiao Jiang; Andong Ji; Daochuan Li; Limei Shi; Mengyu Gao; Na Lv; Ying Zhang; Rong Zhang; Rui Chen; Wen Chen; Yuxin Zheng; Lianhua Cui

doi:10.1016/j.envpol.2021.117792

Mitochondria damage in ambient particulate matter induced cardiotoxicity: Roles of PPAR alpha/PGC-1 alpha signaling

Environ Pollut. 2021 Nov 1:288:117792. doi: 10.1016/j.envpol.2021.117792. Epub 2021 Jul 14.

Authors

Qixiao Jiang¹, Andong Ji¹, Daochuan Li², Limei Shi¹, Mengyu Gao¹, Na Lv³, Ying Zhang¹, Rong Zhang⁴, Rui Chen⁵, Wen Chen², Yuxin Zheng¹, Lianhua Cui⁶

Affiliations

¹ Department of Toxicology, School of Public Health, Qingdao University, Qingdao, China.
² Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, China.
³ Department of Pharmacology, School of Pharmacy, Qingdao University, Qingdao, China.
⁴ Department of Toxicology, School of Public Health, Hebei Medical University, Shijiazhuang, China.
⁵ Department of Toxicology, School of Public Health, Capital Medical University, Beijing, China.
⁶ Department of Toxicology, School of Public Health, Qingdao University, Qingdao, China. Electronic address: qdlhcui@qdu.edu.cn.

PMID: 34280742
DOI: 10.1016/j.envpol.2021.117792

Abstract

Particulate matter (PM) had been associated with cardiotoxicity, while the mechanism of toxicity has yet to be elucidated, with mitochondria dysfunction as a potential candidate. To investigate the potential cardiotoxic effects of ambient PM exposure and assess the damage to cardiac mitochondria, C57/B6 mice were exposed to filtered air or real ambient PM for three or six weeks. Furthermore, to reveal the role of peroxisome proliferators-activated receptor alpha (PPAR alpha) in PM exposure induced cardiotoxicity/mitochondria damage, animals were also co-treated with PPAR alpha agonist WY 14,643 or PPAR alpha antagonist GW 6471. Cardiotoxicity was assessed with echocardiography and histopathology, while mitochondria damage was evaluated with mitochondria membrane potential measurement and transmission electron microscopy. Potential impacts of PM exposure to PPAR alpha signaling were detected with co-immunoprecipitation and western blotting. The results indicated that exposure to ambient PM exposure induced cardiotoxicity in C57/B6 mice, including altered cardiac functional parameters and morphology. Cardiac mitochondria damage is detected, in the form of compromised mitochondria membrane potential and morphology. Molecular investigations revealed disruption of PPAR alpha interaction with peroxisome proliferator-activated receptor gamma coactivator-1A (PGC-1a) as well as altered expression levels of PPAR alpha downstream genes. Co-treatment with WY 14,643 alleviated the observed toxicities, while co-treatment with GW 6471 had mixed results, exaggerating most cardiotoxicity and mitochondrial damage endpoints but alleviating some cardiac functional parameters. Interestingly, WY 14,643 and GW 6471 co-treatment seemed to exhibit similar regulative effects towards PPAR alpha signaling in animals exposed to PM. In conclusion, ambient PM exposure indeed induced cardiotoxicity in C57/B6 mice, in which cardiac mitochondria damage and disrupted PPAR alpha signaling are contributors.

Keywords: Cardiotoxicity; Mitochondria damage; PPAR alpha; Particulate matter.

MeSH terms

Animals
Cardiotoxicity
Mice
Mitochondria
PPAR alpha* / genetics
Particulate Matter* / toxicity
Signal Transduction

Substances

PPAR alpha
Particulate Matter