Open AccessEndothelial Sirtuin 3 Dictates Glucose Transport to Cardiomyocyte and Sensitizes Pressure Overload‐Induced Heart Failure
Author(s) -
Zeng Heng,
He Xiaochen,
Chen JianXiong
Publication year - 2020
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.120.015895
Subject(s) - knockout mouse , pressure overload , medicine , endocrinology , endothelial stem cell , sirtuin 1 , apelin , downregulation and upregulation , heart failure , biology , biochemistry , receptor , cardiac hypertrophy , gene , in vitro
Background Alterations of energetic metabolism are suggested to be an important contributor to pressure overload ( PO )‐induced heart failure. Our previous study reveals that knockout of endothelial Sirtuin 3 ( SIRT 3) alters glycolysis and impairs diastolic function. We hypothesize that endothelial SIRT 3 regulates glucose utilization of cardiomyocytes and sensitizes PO ‐induced heart failure. Methods and Results SIRT 3 endothelial cell knockout mice and their control SIRT 3 LoxP mice were subjected to PO by transverse aortic constriction for 7 weeks. The ratio of heart weight to tibia length was increased in both strains of mice, in which SIRT 3 endothelial cell knockout mice+transverse aortic constriction exhibited more severe cardiac hypertrophy. Coronary blood flow and systolic function were significantly decreased in SIRT 3 endothelial cell knockout mice+transverse aortic constriction compared with SIRT 3 LoxP mice+transverse aortic constriction, as evidenced by lower systolic/diastolic ratio, ejection fraction, and fractional shortening. PO ‐induced upregulation of apelin and glucose transporter 4 were significantly reduced in the hearts of SIRT 3 endothelial cell knockout mice. In vitro , levels of hypoxia‐inducible factor‐1α and glucose transporter 1 and glucose uptake were significantly reduced in SIRT 3 knockout endothelial cells. Furthermore, hypoxia‐induced apelin expression was abolished together with reduced apelin‐mediated glucose uptake in SIRT 3 knockout endothelial cells. Exposure of cardiomyocyte with apelin increased expression of glucose transporter 1 and glucose transporter 4. This was accompanied by a significant increase in glycolysis. Supplement of apelin in SIRT 3 knockout hypoxic endothelial cell media increased glycolysis in the cardiomyocytes. Conclusions Knockout of SIRT 3 disrupts glucose transport from endothelial cells to cardiomyocytes, reduces cardiomyocyte glucose utilization via apelin in a paracrine manner, and sensitizes PO ‐induced heart failure. Endothelial SIRT 3 may regulate cardiomyocyte glucose availability and govern the function of the heart.