Polo-like kinase 2 ameliorates lipopolysaccharide-induced cardiac injury by blocking cardiomyocyte ferroptosis.

Abstract

Background: Polo-like kinase 2 (PLK2) is associated with cardiac fibrosis in patients with atrial fibrillation. However, the role of PLK2 in sepsis-induced cardiac injury has not been fully elucidated. We hypothesize that PLK2 may participate in the progression of sepsis-induced cardiac injury.

Methods: We established a cardiac injury model in C57BL6 mice by injecting lipopolysaccharide (LPS). PLK2 was overexpressed in mice using an adeno-associated virus 9 vector. Cardiac function was evaluated using echocardiography 12 hours after the LPS injection. H9c2 cells were transfected with a PLK2 small interfering RNA. PLK2 was downregulated in the hearts of LPS-treated mice and LPS-stimulated H9c2 cardiomyocytes.

Results: Mice in the LPS group presented aggravated cardiac injury and a reduced survival rate with increased cardiac inflammatory responses and oxidative stress. Moreover, PLK2 relieved LPS-induced cardiac injury and increased the survival rate of the mice by weakening the inflammatory response and decreasing oxidative stress. Moreover, the LPS-induced increase in ferroptosis was inhibited by PLK2 overexpression.LPS caused an increase in inflammation and cell injury in H9c2 cardiomyocytes, and PLK2 silencing aggravated LPS-induced cell injury, inflammation, and oxidative stress. Furthermore, PLK2 overexpression increased the expression levels of the antiferroptotic proteins solute carrier family 7 member 11, glutathione peroxidase 4, and ferritin in heart tissue. PLK2 increased the nuclear NRF2 expression level. Moreover, the overexpression of PLK2 increased the phosphorylation of glycogen synthase kinase 3β and promoted the nuclear translocation of NRF2. NRF2 overexpression relieved cardiac injury in mice induced with LPS. However, NRF2 mitigated the deteriorating effects of PLK2 knockdown in the mouse heart.

Conclusion: PLK2 ameliorated LPS-induced cardiac injury by blocking cardiomyocyte ferroptosis through NRF2 regulation.