Identification of endotrophin as the link between autophagy deficiency and changes in vascular smooth muscle cell function.

Atherosclerotic plaque rupture is responsible for 3.9 million deaths in Europe every year. Thus, further research to determine the underlying molecular mechanisms of this disease is greatly needed in order to define novel treatment strategies. It is known that impaired autophagy, a cellular housekeeping mechanism, has a major impact on the progression and destabilization of atherosclerotic plaques. Therefore, inducing autophagy seems a good therapeutic strategy and we want to specifically target cellular pathways downstream of autophagy. This allows us to modulate the detrimental effects generated by autophagy deficiency, without affecting autophagy itself. In a recent study we observed a strong upregulation of Col6a3 in autophagy deficient vascular smooth muscle cells (VSMCs), which is known to lead to increased levels of endotrophin, a cleavage product of COL6A3. Higher serum endotrophin levels in patients are predictive of cardiovascular events and associated with arterial stiffness, which makes this protein an interesting therapeutic target. Therefore, we aim to identify endotrophin as the key player in the harmful effects of autophagy deficiency on normal VSMC function. In order to reach this objective, we will determine the endotrophin levels produced as a result of autophagy deficiency in VSMCs and define its role in the functional changes (proliferation, migration, collagen production, senescence) that occur in these cells. This is important in understanding how a decline in autophagy can lead to cardiovascular disease. Furthermore, it might result in identifying endotrophin as a novel therapeutic target.

Keywords:VASCULAR SMOOTH MUSCLE CELLS, AUTOPHAGY, ENDOTROPHIN, ATHEROSCLEROSIS

Disciplines:Vascular diseases