iScience (Nov 2023)
Treatment of calcific arterial disease via enhancement of autophagy using GSK343
- Christian L. Lino Cardenas,
- Wanlin Jiang,
- Lova P. Kajuluri,
- Kuldeep Singh,
- Katrina Ostrom,
- Rebecca Li,
- Francois Cherbonneau,
- Sophie Boerboom,
- Claire Birchenough,
- Kangsan Roh,
- Elizabeth L. Chou,
- Zarbafian Shahrooz,
- Christopher Nicholson,
- Adam L. Johnson,
- Sujin Lee,
- Fumito Ichinose,
- Donald B. Bloch,
- Sagar Nigwekar,
- Patrick T. Ellinor,
- Patricia Musolino,
- Mark E. Lindsay,
- Zhixun Dou,
- Clint L. Miller,
- Rajeev Malhotra
Affiliations
- Christian L. Lino Cardenas
- Cardiovascular Research Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Corresponding author
- Wanlin Jiang
- Cardiovascular Research Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Lova P. Kajuluri
- Cardiovascular Research Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Kuldeep Singh
- Cardiovascular Research Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Katrina Ostrom
- Cardiovascular Research Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Rebecca Li
- Cardiovascular Research Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Francois Cherbonneau
- Cardiovascular Research Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Sophie Boerboom
- Cardiovascular Research Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Claire Birchenough
- Cardiovascular Research Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Kangsan Roh
- Cardiovascular Research Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Elizabeth L. Chou
- Cardiovascular Research Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Division of Vascular and Endovascular Surgery, Massachusetts General Hospital, Boston, MA 02114, USA
- Zarbafian Shahrooz
- Cardiovascular Research Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Christopher Nicholson
- Cardiovascular Research Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Adam L. Johnson
- Cardiovascular Research Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Sujin Lee
- Cardiovascular Research Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Fumito Ichinose
- Department of Anesthesia, Critical Care and Pain Medicine at Massachusetts General Hospital, Boston, MA 02114, USA
- Donald B. Bloch
- Department of Anesthesia, Critical Care and Pain Medicine at Massachusetts General Hospital, Boston, MA 02114, USA; Division of Rheumatology, Allergy, and Immunology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
- Sagar Nigwekar
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
- Patrick T. Ellinor
- Cardiovascular Research Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Patricia Musolino
- Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
- Mark E. Lindsay
- Cardiovascular Research Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Zhixun Dou
- Center for Regenerative Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
- Clint L. Miller
- Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA 22908, USA
- Rajeev Malhotra
- Cardiovascular Research Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Corresponding author
- Journal volume & issue
-
Vol. 26,
no. 11
p. 108360
Abstract
Summary: Vascular calcification is a hallmark of atherosclerotic disease and serves as a strong predictor and risk factor for cardiovascular events. Growing evidence suggests that autophagy may play a protective role in early atherosclerosis. The precise effects of autophagy on VSMC-mediated calcification remain unknown. In this study, we utilized multi-omic profiling to investigate impaired autophagy at the transcriptional level as a key driver of VSMC calcification. Our findings revealed that impaired autophagy is an essential determinant of VSMC calcification. We observed that an osteogenic environment affects the open chromatin status of VSMCs, compromising the transcriptional activation of autophagy initiation genes. In vivo experiments involve pharmacological and genetic activation of autophagy using mouse models of spontaneous large (Mgp−/−) and small (Abcc6−/−) artery calcification. Taken together, these data advance our mechanistic understanding of vascular calcification and provide important insights for a broad range of cardiovascular diseases involving VSMC phenotype switch.
