Implementation of programmed cell death in circulating neutrophils and its special characteristics in experimentally induced hyperhomocysteinemia in a setting of thyroid dysfunction.

Cardiovascular (CV) disease continues to be the main cause of morbidity and mortality in worldwide. Hyperhomocysteinemia (HHCy) is a novel metabolic risk factor of vascular damage. In addition to that, there is evidence that HHCy management with folic acid and vitamin B supplements prevents atherosclerosis and its sequelae. Oxidative stress is one of the mechanisms behind the cardiotoxic effects of high homocysteine levels. On the one hand, HHCy facilitates endothelial dysfunction, probably as a result of impaired synthesis and/or inactivation of nitrogen (II) oxide (NO). On the other hand, oxidation of homocysteine is accompanied by formation of reactive oxygen species (ROS), which induce lipid peroxidation in cell membranes and in low density lipoproteins, mitochondrial membrane, secretion of cytochrome C and activation of caspase-3, culminating in apoptosis. Thyroid hormones are known to have a profound effect on CV functions. Hyperthyroidism causes heart rate, myocardial contractility and ejection fraction to increase; this may result in systolic hypertension, systolic heart murmurs, increased left ventricular weight and development of angina and atrial fibrillation with a risk for stroke.
Aim: The aim of our work was to investigate into the special aspects that characterize implementation of programmed cell death in circulating neutrophils of HHCy rats either without comorbidities or with hyper- or hypothyroidism.
Materials and Methods: Prolonged hyperthyroidism and hypothyroidism were modeled in experimental rats by dosing the animals with Lthyroxine and thiamazole, respectively, for 21 days, and prolonged with HHCy administered with excessive exogenous HCy, for 21 days. Prolonged HHCy rats with hyper- or hypothyroidism were observed.
Results: We have found the count of circulating neutrophils with increased ROS production and reduced transmembrane mitochondrial potential to be significantly increased in rats with HHCy compared to control animals, which suggests prooxidant properties of HCy and its ability to cause mitochondrial dysfunction. The intensity of ROS production by circulating neutrophils in hyperthyroid animals with HHCy was not significantly different from that in hyperthyroid rats without HHCy. In hypothyroid rats with HHCy, ROS production by circulating neutrophils was significantly higher compared to the control group. HCys increased ROS generation in kidney mitochondria while strongly decreasing it in liver, heart and brain mitochondria showing that the changes are tissue-specific. We have found the count of circulating neutrophils with signs of apoptosis to be increased in rats with HHCy compared to the control group.
Conclusions: Experimentally induced HHCy is accompanied by hyperproduction of reactive oxygen species and by impaired integrity of external mitochondrial membrane, which results in initiation of apoptotic cell death. The deficiency of thyroid hormones enhances initiation of programmed cell death.
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