National Pirogov Memorial Medical University, Vinnytsya, Ukraine.
I.Ya. Gorbachevsky Ternopil National Medical University of Moh, Ukraine.
Pol Merkur Lekarski. 2020 Dec 22;48(288):437-442.
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.
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.
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.
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.
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.
我们的工作旨在研究高同型半胱氨酸血症（HHcy）大鼠循环中性粒细胞中程序性细胞死亡的特殊特征，无论是否伴有合并症或伴有甲状腺功能亢进或甲状腺功能减退症。
通过给予实验大鼠左旋甲状腺素和他巴唑分别 21 天来延长甲状腺功能亢进和甲状腺功能减退症，并给予过量外源性 HCy 延长 HHcy 大鼠 21 天，建立延长的 HHcy 大鼠伴有高或低甲状腺功能。观察延长的 HHcy 大鼠伴有高或低甲状腺功能。
我们发现，与对照组相比，HHcy 大鼠循环中性粒细胞中 ROS 产生增加和跨膜线粒体电位降低的中性粒细胞计数显著增加，这表明 HCy 具有促氧化剂特性及其引起线粒体功能障碍的能力。HHcy 甲状腺功能亢进大鼠循环中性粒细胞中 ROS 的产生强度与无 HHcy 的甲状腺功能亢进大鼠无显著差异。在 HHcy 甲状腺功能减退大鼠中，循环中性粒细胞中 ROS 的产生明显高于对照组。HCys 增加了肾线粒体中的 ROS 生成，而强烈降低了肝、心和脑线粒体中的 ROS 生成，表明变化是组织特异性的。我们发现与对照组相比，HHcy 大鼠循环中性粒细胞中出现凋亡迹象的中性粒细胞计数增加。
实验诱导的 HHcy 伴有活性氧的过度产生和外部线粒体膜完整性受损，导致细胞凋亡的起始。甲状腺激素缺乏症增强了程序性细胞死亡的起始。
