NOX2-induced oxidative stress triggers cardiac hypercontractility during severe malaria

Malaria is a life-threatening disease that can lead to severe systemic complications and remains endemic in many countries. Clinical reports indicate that malaria can also cause cardiac disorders, which increases morbidity and mortality associated with the disease. While systemic oxidative stress markers are positively correlated with malaria severity, the role of reactive oxygen species (ROS) in heart alterations during malaria remains unclear.

In this study, the time course of heart function and local redox balance in male Balb/c mice infected with Plasmodium chabaudi was determined. Additionally, the role of NOX2 was investigated using apocynin and NOX2 knockout mice (NOX2^-/-). Cardiac contractility was evaluated using isolated Langendorff heart preparation. Redox analysis included lipid peroxidation by TBARS, antioxidant capacity, ROS production by DHE, and levels of cytokines.

Isolated hearts from P. chaubaudi-infected mice presented higher contraction indexes at baseline and under isoprenaline stimulation throughout the course of the disease. This was associated with increased levels of TBARS and reduced superoxide dismutase (SOD) activity. Apocynin treatment (30 mg/kg/day) and NOX2 deletion reversed malaria-induced cardiac hypercontractility without interfering with parasitemia and other signs of the infection. Additionally, apocynin treatment mitigated cardiac oxidative stress and reduced the cardiac upregulation of pro-inflammatory cytokines such as IL-1β and IL-6 during malaria.

Therefore, NOX2 leads to hyperdynamic hearts in malaria by inducing local oxidative stress and inflammation.