Abstract
Age-related diseases such as cardiovascular (CV) disease have a substantial impact on our quality of life. The aging vasculature is characterized by arterial stiffness, which is an independent predictor of CV complications. There is accumulating evidence that loss of autophagy, a cellular housekeeping mechanism, facilitates vascular aging. Recent literature describes that endotrophin (ETP) serum levels (a cleavage product of COL6A3) are associated with arterial stiffness and CV events. Furthermore, we have observed that autophagy deficiency in vascular smooth muscle cells (VSMCs) results in a higher expression of ETP. However, an in-depth analysis of the link between ETP and autophagy and how this affects vascular aging is lacking. Therefore, we aim to investigate if ETP accelerates vascular aging and whether it contributes to the detrimental effects of autophagy deficiency in VSMCs. This will answer three research questions: (1) What are the biological effects of ETP on vascular cell function, and do they explain some of the detrimental effects of VSMC autophagy deficiency? (2) Can ETP contribute to accelerated vascular aging in mice? (3) Does defective VSMC autophagy exert its main effects on the vascular wall through enhanced expression of ETP? Overall, this project will bring us one step closer in understanding how an age-related decline in autophagy can lead to CV disease and might result in identifying ETP as a novel therapeutic target.
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