TRα inhibits arterial renin-angiotensin system expression and prevents cholesterol accumulation in vascular smooth muscle cells.

OBJECTIVES:The tissue renin-angiotensin system (tRAS) plays a key role in the maintenance of cellular homeostasis but is also implicated in atherosclerosis. Thyroid hormone (TH) contributes, via genomic effects, to control of tRAS gene expression in the arterial wall and vascular smooth muscle cells (VSMCs). We investigated the specific functions of TH receptors-α and -β (TRα and TRβ) on tRAS gene expression in the aorta and VSMCs, and the potential protective effect of TRα against atherosclerosis. MATERIAL AND METHODS:Using aorta and cultured aortic VSMCs from TRα and TRβ deficient mice, tRAS gene expression was analyzed by determining mRNA levels on real-time PCR. Gene regulation under cholesterol loading mimicking atherosclerosis conditions was also examined in VSMCs in vitro. RESULTS:TRα deletion significantly increased expression of angiotensinogen (AGT) and angiotensin II receptor type 1 subtype a (AT₁R_a) at transcriptional level in aorta, a tissue with high TRα expression level. TRα activity thus seems to be required for maintenance of physiological levels of AGTand AT₁R_aexpression in the arterial wall. In addition, during cholesterol loading, TRα deletion significantly increased cholesterol content in VSMCs, with a weaker decrease in AGTexpression. CONCLUSION:TRα seems to have an inhibitory impact on AGTand AT₁R_aexpression, and loss of TRα function in TRα^0/0 mice increases tRAS expression in the aortic wall. More importantly, TRα deletion significantly increases VSMC cholesterol content. Our results are consistent with a protective role of TRα against atherosclerosis.

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