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Open AccessArticle

Inducible Cardiac-Specific Deletion of Sirt1 in Male Mice Reveals Progressive Cardiac Dysfunction and Sensitization of the Heart to Pressure Overload

1
UMR-S 1180, Inserm, Univ. Paris-Sud, Université Paris-Saclay, 92290 Châtenay-Malabry, France
2
INSERM UMR_S 999, Hôpital Marie Lannelongue, 92350 Le Plessis Robinson, France
3
Université Versailles St. Quentin, Université Paris-Saclay, 78035 Versailles, France
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2019, 20(20), 5005; https://doi.org/10.3390/ijms20205005
Received: 17 September 2019 / Revised: 4 October 2019 / Accepted: 8 October 2019 / Published: 10 October 2019
(This article belongs to the Special Issue Heart Failure: From Molecular Basis to Therapy)
Heart failure is associated with profound alterations of energy metabolism thought to play a major role in the progression of this syndrome. SIRT1 is a metabolic sensor of cellular energy and exerts essential functions on energy metabolism, oxidative stress response, apoptosis, or aging. Importantly, SIRT1 deacetylates the peroxisome proliferator-activated receptor gamma co-activator 1α (PGC-1α), the master regulator of energy metabolism involved in mitochondrial biogenesis and fatty acid utilization. However, the exact role of SIRT1 in controlling cardiac energy metabolism is still incompletely understood and conflicting results have been obtained. We generated a cardio-specific inducible model of Sirt1 gene deletion in mice (Sirt1ciKO) to decipher the role of SIRT1 in control conditions and following cardiac stress induced by pressure overload. SIRT1 deficiency induced a progressive cardiac dysfunction, without overt alteration in mitochondrial content or properties. Sixteen weeks after Sirt1 deletion an increase in mitochondrial reactive oxygen species (ROS) production and a higher rate of oxidative damage were observed, suggesting disruption of the ROS production/detoxification balance. Following pressure overload, cardiac dysfunction and alteration in mitochondrial properties were exacerbated in Sirt1ciKO mice. Overall the results demonstrate that SIRT1 plays a cardioprotective role on cardiac energy metabolism and thereby on cardiac function. View Full-Text
Keywords: Sirtuin 1; heart; mitochondria; cardiac function Sirtuin 1; heart; mitochondria; cardiac function
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Sanz, M.-N.; Grimbert, L.; Moulin, M.; Gressette, M.; Rucker-Martin, C.; Lemaire, C.; Mericskay, M.; Veksler, V.; Ventura-Clapier, R.; Garnier, A.; Piquereau, J. Inducible Cardiac-Specific Deletion of Sirt1 in Male Mice Reveals Progressive Cardiac Dysfunction and Sensitization of the Heart to Pressure Overload. Int. J. Mol. Sci. 2019, 20, 5005.

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