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Cardiovascular Diabetology
Published in: Cardiovascular Diabetology 1/2018

Open Access 01-12-2018 | Original investigation

Regulation of diabetic cardiomyopathy by caloric restriction is mediated by intracellular signaling pathways involving ‘SIRT1 and PGC-1α’

Authors: Maayan Waldman, Keren Cohen, Dor Yadin, Vadim Nudelman, Dan Gorfil, Michal Laniado-Schwartzman, Ran Kornwoski, Dan Aravot, Nader G. Abraham, Michael Arad, Edith Hochhauser

Published in: Cardiovascular Diabetology | Issue 1/2018

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Abstract

Background

Metabolic disorders such as obesity, insulin resistance and type 2 diabetes mellitus (DM2) are all linked to diabetic cardiomyopathy that lead to heart failure. Cardiomyopathy is initially characterized by cardiomyocyte hypertrophy, followed by mitochondrial dysfunction and fibrosis, both of which are aggravated by angiotensin. Caloric restriction (CR) is cardioprotective in animal models of heart disease through its catabolic activity and activation of the expression of adaptive genes. We hypothesized that in the diabetic heart; this effect involves antioxidant defenses and is mediated by SIRT1 and the transcriptional coactivator PGC-1α (Peroxisome proliferator-activated receptor-γ coactivator).

Methods

Obese Leptin resistant (db/db) mice characterized by DM2 were treated with angiotensin II (AT) for 4 weeks to enhance the development of cardiomyopathy. Mice were concomitantly either on a CR diet or fed ad libitum. Cardiomyocytes were exposed to high levels of glucose and were treated with EX-527 (SIRT1 inhibitor). Cardiac structure and function, gene and protein expression and oxidative stress parameters were analyzed.

Results

AT treated db/db mice developed cardiomyopathy manifested by elevated levels of serum glucose, cholesterol and cardiac hypertrophy. Leukocyte infiltration, fibrosis and an increase in an inflammatory marker (TNFα) and natriuretic peptides (ANP, BNP) gene expression were also observed. Oxidative stress was manifested by low SOD and PGC-1α levels and an increase in ROS and MDA. DM2 resulted in ERK1/2 activation. CR attenuated all these deleterious perturbations and prevented the development of cardiomyopathy. ERK1/2 phosphorylation was reduced in CR mice (p = 0.008). Concomitantly CR prevented the reduction in SIRT activity and PGC-1α (p < 0.04). Inhibition of SIRT1 activity in cardiomyocytes led to a marked reduction in both SIRT1 and PGC-1α. ROS levels were significantly (p < 0.03) increased by glucose and SIRT1 inhibition.

Conclusion

In the current study we present evidence of the cardioprotective effects of CR operating through SIRT1 and PGC-1 α, thereby decreasing oxidative stress, fibrosis and inflammation. Our results suggest that increasing SIRT1 and PGC-1α levels offer new therapeutic approaches for the protection of the diabetic heart.
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Metadata
Title
Regulation of diabetic cardiomyopathy by caloric restriction is mediated by intracellular signaling pathways involving ‘SIRT1 and PGC-1α’
Authors
Maayan Waldman
Keren Cohen
Dor Yadin
Vadim Nudelman
Dan Gorfil
Michal Laniado-Schwartzman
Ran Kornwoski
Dan Aravot
Nader G. Abraham
Michael Arad
Edith Hochhauser
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Cardiovascular Diabetology / Issue 1/2018
Electronic ISSN: 1475-2840
DOI
https://doi.org/10.1186/s12933-018-0754-4

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