methimazole and Hypercholesterolemia

Free circulating extracellular DNA, plasma activities of matrix metalloproteinases in hypothyroid rats, and ultrastructural changes in the myocardium were studied under conditions of experimental hypercholesterolemia. For suppression of thyroid function, the animals received antithyroid drug mercazolyl under conditions of cholesterol diet. Hypercholesterolemia in hypothyroid rats (thyroxine concentration 2-fold below the normal) was paralleled by a pronounced increase of the concentration of free circulating extracellular DNA and total matrix metalloproteinases 2 and 7 activity. These changes were associated with lytic and destructive changes in cardiomyocytes and blood capillary endotheliocytes. Changes in the cardiomyocyte and endotheliocyte ultrastructure were more pronounced in hypothyroid rats.

Topics: Animals; DNA; Hypercholesterolemia; Hypothyroidism; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 7; Matrix Metalloproteinases; Methimazole; Myocardium; Rats; Rats, Wistar

Chronic hypothyroidism is associated with an increased risk for cardiovascular disease attributed, in part, to increased serum cholesterol and atherosclerosis. Decreased hepatic activity of cholesterol 7a-hydroxylase (CYP7A1) is thought to contribute to hypercholesterolemia in hypothyroidism. The endoplasmic reticulum (ER) has been shown to be a central organelle, and it is the location of CYP7A1 in hepatocyte. The aim of the present study was to determine whether the expression of CYP7A1 mRNA and protein could be decreased and whether ER could undergo morphological changes in a rodent model of chronic hypothyroidism induced by methimazole (MMI). Male Wistar rats were treated with MMI (0.04% wt/vol) or regular water for 14 weeks. Hepatic CYP7A1 mRNA was analyzed on quantitative real-time polymerase chain reaction (PCR). Hepatic CYP7A1 protein expression was assessed on western blot. In conjunction with these molecular biological assessments the morphology of ER was evaluated on transmission electron microscopy (TEM). Serum total cholesterol increased significantly compared to controls and was associated with decreased CYP7A1 mRNA and protein, and TEM indicated remarkable dilation of ER in hepatocytes in the chronic hypothyroid rats. These findings suggest that a relationship between the decreased expression of hepatic CYP7A1 mRNA and protein and dilated ER could exist, which may contribute to hypercholesterolemia in chronic hypothyroidism.

Topics: Animals; Blotting, Western; Cholesterol 7-alpha-Hydroxylase; Chronic Disease; Disease Models, Animal; Endoplasmic Reticulum; Gene Expression Regulation, Enzymologic; Hepatocytes; Hypercholesterolemia; Hypothyroidism; Liver; Male; Methimazole; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger