The role of hepatic glutaminolysis in atherosclerosis
Cardiovascular diseases are the leading cause of death worldwide with 17 million deaths each year and represent a major public health challenge. Despite existing therapies aimed at restoring lipid homeostasis, the prevalence of these diseases keeps increasing and new targets must be find. Recently, new factors have been identified as potential actors in the development of atherosclerotic plaques. Among them, glutamine, a conditionally essential amino acid, and its metabolism have been linked to the incidence of cardiovascular disease and inflammation. Two major enzymes are involved in controlling the flow of this amino acid within our body. Glutaminase 2 (GLS2) metabolizes glutamine into glutamate and the reverse reaction is mediated by glutamine synthetase (GS).
During our study, we first studied the effect of their inhibition in a mouse model of atherosclerosis with adeno-associated virus (AAV) injection or methionine sulfoximine. While GS inhibition has a little impact on lesion development, GLS2 deficiency leads to an increase in atherosclerotic plaque size. At the same time, plasma glutamine is increased. There was no major change in classical cardiovascular risk factors or even inflammation. By performing analyzes of the transcriptional profile of the liver and aortas of GLS2 KO animals, we noticed that many genes involved in the remodeling of the extracellular matrix and in the cell/matrix interaction were deregulated. Dedicated stainings of the plaques corroborated the RNA sequencing and identified regulation of key matrix-modulating enzymes supporting the hypothesis of a weakening of the extracellular matrix. Especially, we found an increase in the activity of transglutaminase 2 (TGM2), one of the pivotal regulator of matrix integrity. We next investigated the therapeutic opportunity by overexpressing hepatic GLS2. In our mouse model overexpressing the enzyme, we observed a decrease in atherosclerotic plaque size as well as a decrease in plasma glutamine.
GLS2 seems to be a new player in the prevention of atherosclerosis not only by maintaining cell homeostasis but also by guaranteeing the environment integrity in which they evolve. It would be interesting to explore this new target at a time when therapies seem to be running out of steam.
Atherosclerosis, Glutamine, Glutaminase, Cardiovascular, Metabolism, Liver
President of the jury:
Prof. Fanny BUREL-VANDENBOS, PU-PH, University Côte d'Azur-LCAP, Nice
Dr. Muriel LAFFARGUE, DR, Toulouse III-I2MC University, Toulouse
Dr. Delphine EBERLÉ, MCU-HDR, University of Lille-Institut Pasteur, Lille
Prof. Bruno FÈVE, PU-PH, Sorbonne University-UPMC-CRSA, Paris
Dr. Fabienne FOUFELLE, DR, Sorbonne University-CRC, Paris
PhD supervisor :
Dr. Laurent YVAN-CHARVET, DR, University Côte-d'Azur-C3M Inserm U1065, Nice