Sirtuin 1 aggravates hypertrophic heart failure caused by pressure overload via shifting energy metabolism

Tran Ngoc Van Le; Linda Ines Zoungrana; Hao Wang; Mohammad Kasim Fatmi; Di Ren; Meredith Krause-Hauch; Ji Li

doi:10.1016/j.bbrc.2022.11.014

Sirtuin 1 aggravates hypertrophic heart failure caused by pressure overload via shifting energy metabolism

Biochem Biophys Res Commun. 2022 Dec 31:637:170-180. doi: 10.1016/j.bbrc.2022.11.014. Epub 2022 Nov 13.

Authors

Tran Ngoc Van Le¹, Linda Ines Zoungrana¹, Hao Wang¹, Mohammad Kasim Fatmi¹, Di Ren¹, Meredith Krause-Hauch², Ji Li³

Affiliations

¹ Department of Surgery, USF Health Heart Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, 33612, USA.
² Department of Surgery, USF Health Heart Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, 33612, USA; James A. Haley Veterans Hospital, Tampa, FL, 33612, USA.
³ Department of Surgery, USF Health Heart Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, 33612, USA; James A. Haley Veterans Hospital, Tampa, FL, 33612, USA. Electronic address: jili@usf.edu.

Abstract

Sirtuin1 (SIRT1) is involved in regulating substrate metabolism in the cardiovascular system. Metabolic homeostasis plays a critical role in hypertrophic heart failure. We hypothesize that cardiac SIRT1 can modulate substrate metabolism during pressure overload-induced heart failure. The inducible cardiomyocyte Sirt1 knockout (icSirt1^-/-) and its wild type littermates (Sirt1^f/f) C57BL/6J mice were subjected to transverse aortic constriction (TAC) surgery to induce pressure overload. The pressure overload induces upregulation of cardiac SIRT1 in Sirt1^f/f but not icSirt1^-/- mice. The cardiac contractile dysfunctions caused by TAC-induced pressure overload occurred in Sirt1^f/f but not in icSirt1^-/- mice. Intriguingly, Sirt1^f/f heart showed a drastic reduction in systolic contractility and electric signals during post-TAC surgery, whereas icSirt1^-/- heart demonstrated significant resistance to pathological stress by TAC-induced pressure overload as evidenced by no significant changes in systolic contractile functions and electric properties. The targeted proteomics showed that the pressure overload triggered downregulation of the SIRT1-associated IDH2 (isocitrate dehydrogenase 2) that resulted in increased oxidative stress in mitochondria. Moreover, metabolic alterations were observed in Sirt1^f/f but not in icSirt1^-/- heart in response to TAC-induced pressure overload. Thus, SIRT1 interferes with metabolic homeostasis through mitochondrial IDH2 during pressure overload. Inhibition of SIRT1 activity benefits cardiac functions under pressure overload-related pathological conditions.

Keywords: Mitochondria; Pressure overload; SIRT1; Substrate metabolism.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Aortic Valve Stenosis*
Constriction, Pathologic
Energy Metabolism
Heart Failure* / etiology
Hypertrophy
Mice
Mice, Inbred C57BL
Myocytes, Cardiac
Sirtuin 1* / metabolism

Substances

Sirtuin 1
Sirt1 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding