Protective role of chaperone-mediated autophagy against atherosclerosis
Julio Madrigal‐Matute, Jenny de Bruijn, Kim van Kuijk, Dario F. Riascos‐Bernal, Antonio Díaz, Inmaculada Tasset, Adrián Martín‐Segura, Marion J. Gijbels, Bianca Sander, Susmita Kaushik, Erik A.L. Biessen, Simoni Tiano, Mathieu Bourdenx, Gregory J. Krause, Ian R McCracken, Andrew H. Baker, Han Jin, Nicholas Sibinga, Jose Javier Bravo‐Cordero, Fernando Macián, Rajat Singh, Patrick C.N. Rensen, Jimmy F.P. Berbée, Gerard Pasterkamp, Judith C. Sluimer, Ana María Cuervo
Abstract
Chaperone-mediated autophagy (CMA) contributes to regulation of energy homeostasis by timely degradation of enzymes involved in glucose and lipid metabolism. Here, we report reduced CMA activity in vascular smooth muscle cells and macrophages in murine and human arteries in response to atherosclerotic challenges. We show that in vivo genetic blockage of CMA worsens atherosclerotic pathology through both systemic and cell-autonomous changes in vascular smooth muscle cells and macrophages, the two main cell types involved in atherogenesis. CMA deficiency promotes dedifferentiation of vascular smooth muscle cells and a proinflammatory state in macrophages. Conversely, a genetic mouse model with up-regulated CMA shows lower vulnerability to proatherosclerotic challenges. We propose that CMA could be an attractive therapeutic target against cardiovascular diseases.