The Pathogenetic Role of Heme in Pregnancy-Induced Hypertension-like Disease in Ewes

Toxicosis syndrome of fasting pregnant ewes has a close similarity to human preeclampsia (hypertension, albuminuria). The common etiological factor might be oxidative hemolysis and heme-induced endothelial damage. Ewes (5 starving, 5 control) at 130–135 gestational days with a 96-h fasting period followed by refeeding were used. Blood pressure, platelet count, electrolytes, kidney and liver function parameters, as well as plasma glucose, hemoglobin/heme, free thiol groups and Trolox equivalent antioxidant capacity, and plasma iron and ferritin levels were measured. Statistical significance was assessed using Student'sttest (P< 0.05). Besides hypertension and renal disturbances, hemolysis, elevated liver enzymes and low platelet count, characteristic of human HELLP syndrome, were also present. In the first 24 h of glucose deprivation there was a significant rise in both the plasma hemoglobin/heme and indirect bilirubin concentrations. The antioxidant free thiol levels decreased significantly the next day, without any change in the total antioxidant capacity of the plasma. While the loss of calcium and magnesium levels related to the similarity to preeclampsia, reduced plasma iron concentrations referred to species differences in iron homeostasis. An oxidative stress causing hemolysis in a glucose-6-phosphate dehydrogenase-deficient animal model was proven by the loss of free thiols after glucose deprivation. The activation of the oxidative stress protein heme oxygenase was a signal of endothelial cell injury, the primary cause of pregnancy-induced hypertension.