Thyromimetics: Novel Drugs against Atherosclerosis

An inverse relation between high density lipoprotein (HDL) cholesterol and the incidence of coronary heart disease (CHD) has been firmly established in numerous epidemiologic studies. The reverse cholesterol transport is one of the major pathways determining plasma levels and metabolism of HDL particles. Key proteins within this pathway include cholesteryl ester transfer protein (CETP) and scavenger receptor class B type I (SR-BI). Thyroid hormones have been found to be associated with plasma levels of low-density lipoprotein (LDL) and HDL-cholesterol. The known cardiotoxic effects of thyroid hormones restrict their use as hypolipidemic drugs. However, it is conceivable that liver-selective thyromimetic substances may act in a similar way as thyroid hormones and, may therefore represent novel drugs for treatment of dyslipemias and for prevention of atherosclerosis in humans. In this application, we propose to investigate effects of thyromimetic substance KAT-681 in New Zealand White rabbits, an animal model displaying a manlike lipoprotein profile and being susceptible to atherosclerosis. These studies will include measurement of lipoprotein profiles and HDL metabolism, and, most importantly, the impact of KAT-681 on the development of atherosclerosis in these animals. We plan to continue our in vivo experiments in mice investigating the influence of KAT-681 on expression of key proteins of HDL-metabolism, on lipoprotein profiles, as well as on radiolabeled HDL-turnover and on in vivo reverse cholesterol transport. To further delineate the specific role of LDL-receptor and SR-BI in this scenario these studies are proposed to include experiments employing corresponding knock-out mouse models. Our studies are a prerequisite to define the role of thyromimetic substances as potential novel drugs for treatment of dyslipemias and for prevention of atherosclerosis in humans.

An inverse relation between high density lipoprotein (HDL) cholesterol and the incidence of coronary heart disease (CHD) has been firmly established in numerous epidemiologic studies. The reverse cholesterol transport is one of the major pathways determining plasma levels and metabolism of HDL particles. Key proteins within this pathway include cholesteryl ester transfer protein (CETP) and scavenger receptor class B type I (SR-BI). Thyroid hormones have been found to be associated with plasma levels of low-density lipoprotein (LDL) and HDL-cholesterol. The known cardiotoxic effects of thyroid hormones restrict their use as hypolipidemic drugs. However, it is conceivable that liver-selective thyromimetic substances may act in a similar way as thyroid hormones and, may therefore represent novel drugs for treatment of dyslipemias and for prevention of atherosclerosis in humans. In this application, we propose to investigate effects of thyromimetic substance KAT-681 in New Zealand White rabbits, an animal model displaying a manlike lipoprotein profile and being susceptible to atherosclerosis. These studies will include measurement of lipoprotein profiles and HDL metabolism, and, most importantly, the impact of KAT-681 on the development of atherosclerosis in these animals. We plan to continue our in vivo experiments in mice investigating the influence of KAT-681 on expression of key proteins of HDL-metabolism, on lipoprotein profiles, as well as on radiolabeled HDL-turnover and on in vivo reverse cholesterol transport. To further delineate the specific role of LDL-receptor and SR-BI in this scenario these studies are proposed to include experiments employing corresponding knock-out mouse models. Our studies are a prerequisite to define the role of thyromimetic substances as potential novel drugs for treatment of dyslipemias and for prevention of atherosclerosis in humans.