Rôle du récepteur aux hormones thyroïdiennes TRalpha dans le développement de l'athérosclérose – aTHeRoma

The impact of loss of TRa function on two other risk factors for atherosclerosis was evaluated in our genetically modified mouse model, namely hypertension and inflammation. This aspect of the work combined experiments of classical physiology (blood pressure measurements, effort test, determination of the concentration of different inflammatory molecules in the blood) and ultrasound technology (to detect atherosclerosis lesion formation) but also ex vivo experiment in cell culture (to characterize in more details TRa function in two particular cell types of interest: macrophage and the vascular smooth muscle cell). For human studies, the impact of common polymorphisms in the TRa gene has been analyzed in individuals from two cohorts of patients suffering from cardiovascular diseases, for which we also have paired control individuals. The aim here was to determine whether among the polymorphisms were preferentially found in one of the two groups (patients or controls).

In mouse TRa deletion is associated with an acceleration of atherosclerosis development, without modification of circulating levels of cholesterol and as we were able to demonstrate here without provoking hypertension. We also show here that the absence of TRa correlates with a pro-inflammatory status, characterized by an increased production of cytokines in different tissues such as aortas and macrophages. However no association could be found between the natural variability of the TRa locus and the incidence of atherosclerosis in humans.

The new “anti-inflammatory” role identified here for TRa could also occur in other tissues and thus involved TRa in other inflammatory diseases. The molecular mecanisms involved in this new process are currently poorly understood. Studies concerning this new function are underway in collaboration with a new team in Lyon. In the long run, modulating TRa function could allow to regulate inflammatory processes in pathological situations.

Two multi-partner manuscripts have been written from the results obtained in this program, one is already published in American Journal of Hypertension (Goumidi et al. 2011) and the other one is currently submitted to PNAS (Billon et al.). All these results have been presented at several national and international meetings.