Cardiac-specific overexpression of Klotho attenuates paraquat-induced myocardial injury by enhancing the Nrf2/ARE signaling pathway.

Abstract

Paraquat, a widely used herbicide, is known to induce oxidative stress and inflammation, which leads to myocardial injury. Klotho, a protein with antioxidative and anti-inflammatory properties, has garnered as a potential cardioprotective factor. This study aimed to investigate whether cardiac-specific overexpression of klotho mitigates paraquat-induced myocardial injury through the activation of the NF-E2-related factor-2 (Nrf-2)/antioxidant response element (ARE) signaling pathway. Our results revealed that both mRNA and protein expressions of Klotho were significantly reduced in the myocardial tissue of paraquat-exposed rats. However, cardiac-specific overexpression of Klotho significantly restored Klotho levels and attenuated paraquat-induced myocardial injury, as evidenced by the decreased lactate dehydrogenase (LDH) and cardiac troponin I (cTnI) contents, and creatine kinase (CK) activity, alongside with apoptosis. Furthermore, cardiac-specific overexpression of Klotho inhibited oxidative stress and inflammation in myocardial tissue of paraquat-subjected rats. Mechanistically, Klotho activated of the Nrf2/ARE signaling pathway, upregulating cytoprotective genes such as NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase-1 (HO-1), glutamate cysteine ligase catalytic (GCLC) subunit, and glutamate cysteine ligase modifier (GCLM) subunit. Our findings indicate that Klotho protects against paraquat-induced myocardial injury by suppressing oxidative stress and inflammation, primarily via the activation of the Nrf2/ARE signaling pathway. These results underscore the potential therapeutic role of Klotho in preventing paraquat-induced myocardial damage.