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

doi:10.1016/j.isci.2023.108360

Treatment of calcific arterial disease via enhancement of autophagy using GSK343

iScience. 2023 Oct 29;26(11):108360. doi: 10.1016/j.isci.2023.108360. eCollection 2023 Nov 17.

Authors

Christian L Lino Cardenas¹, Wanlin Jiang¹, Lova P Kajuluri¹, Kuldeep Singh¹, Katrina Ostrom¹, Rebecca Li¹, Francois Cherbonneau¹, Sophie Boerboom¹, Claire Birchenough¹, Kangsan Roh¹, Elizabeth L Chou^{1

2}, Zarbafian Shahrooz¹, Christopher Nicholson¹, Adam L Johnson¹, Sujin Lee¹, Fumito Ichinose³, Donald B Bloch^{3

4}, Sagar Nigwekar⁵, Patrick T Ellinor¹, Patricia Musolino⁶, Mark E Lindsay¹, Zhixun Dou⁷, Clint L Miller⁸, Rajeev Malhotra¹

Affiliations

¹ Cardiovascular Research Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
² Division of Vascular and Endovascular Surgery, Massachusetts General Hospital, Boston, MA 02114, USA.
³ Department of Anesthesia, Critical Care and Pain Medicine at Massachusetts General Hospital, Boston, MA 02114, USA.
⁴ Division of Rheumatology, Allergy, and Immunology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
⁵ Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
⁶ Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
⁷ Center for Regenerative Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
⁸ Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA 22908, USA.

Abstract

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.

Keywords: Cardiovascular medicine; Human Genetics; Molecular physiology.

Abstract

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