Implicações da nadph oxidase para as alterações cardíacas induzidas pela malária grave

Abstract

Malaria is an endemic disease in the northern region of Brazil, which can course with severe systemic complications. Although rare, cardiac disorders are associated with higher morbidity and mortality for malaria. Oxidative stress is a known factor triggering cardiac injury. Nevertheless, the relationship between heart damage and oxidative stress during severe malaria is unclear. In this study, male BALB/c mice were infected with 106 red blood cells infected with Plasmodium chabaudi and they were evaluated at 7, 14 e 28 days post-infection (dpi). Cardiac function was assessed ex vivo by the Langendorff method. Cardiac lipid peroxidation, superoxide dismutase (SOD), catalase, and reduced glutathione levels (GSH) were determined by colorimetric standard methods. Body weight loss, anemia, hepatomegaly, and splenomegaly were found at 7 and 14 dpi. Perfused hearts of infected mice had greater basal left ventricular developed pressure (LVDP), maximum (dP/dtmax) and minimum (dP/dtmin) derivatives of left ventricular pressure, as well as hyperresponsiveness to isoprenaline compared to the control (uninfected). Increased lipid peroxidation and reduced SOD activity was observed at 14 dpi. At 28 dpi, heart function was normalized, followed by no parasitemia. To analyze the role of nicotinamide adenine dinucleotide phosphate oxidase (NOX) in heart dysfunction during experimental malaria, mice were treated with apocynin from the 7th to 14th dpi (30 mg/kg/day, gavage). Local oxidative stress and cytokine levels were determined. Apocynin reversed cardiac hypercontractility at baseline, under a progressive filling pressure increment and isoprenaline stimulation. Also, the treatment reduced oxidative stress and pro-inflammatory cytokines in the cardiac tissue, with no effects in the clinical signs of the disease. To confirm the involvement of NOX2 isoform in heart hypercontractility, NOX2 knockout mice (NOX2 -/-) were inoculated with parasitized red blood cells. NOX2-/- infected mice developed similar parasitemia and other clinical signals, however, were protected from the cardiac hypercontractility induced by malaria. Therefore, NOX2 inhibition selectively reverses heart alterations during acute phase of malaria. These show that NOX is the main cardiac source of reactive oxygen species during severe malaria, and its inhibition protects animals from cardiac changes.