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

Abstract

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.

Mitochondrial ROS-Modulated mtDNA: A Potential Target for Cardiac Aging

“…SIRT1 deletion increases both mtROS and the rate of oxidative damage. After pressure overload, SIRT1 gene deletion mice have exhibited exacerbated cardiac dysfunction and alterations of mitochondrial properties [101]. Melatonin ameliorates myocardial I/R injury via SIRT1 activation [99].…”

Longevity genes, cardiac ageing, and the pathogenesis of cardiomyopathy: implications for understanding the effects of current and future treatments for heart failure

“… 17 , 18 Cardiac-specific deletion of SIRT1 in mice augments mitochondrial production of reactive oxygen species, enhances oxidative and endoplasmic reticulum stress, and sensitizes the heart to pressure overload and ischaemia/reperfusion injury, leading to cardiac dysfunction and cardiomyopathy. 19–21 Conversely, SIRT1 enrichment or activation improves cardiac function and prevents adverse ventricular remodelling following experimental infarction 22 , 23 ; mitigates cardiac injury and mitochondrial dysfunction produced by diverse cellular stresses 24–26 ; and ameliorates fibrosis produced by pressure overload. 27 In experimental models of heart failure, activation of SIRT1 restores the functionality of sarco-endoplasmic reticulum Ca 2+ -ATPase and improves cardiac function, 28 , 29 whereas suppression of SIRT1 decreases angiogenesis and leads to systolic and diastolic abnormalities.…”

“… 27 In experimental models of heart failure, activation of SIRT1 restores the functionality of sarco-endoplasmic reticulum Ca 2+ -ATPase and improves cardiac function, 28 , 29 whereas suppression of SIRT1 decreases angiogenesis and leads to systolic and diastolic abnormalities. 19 , 21 , 30 …”

MicroRNA-29b-3p Promotes Human Retinal Microvascular Endothelial Cell Apoptosis via Blocking SIRT1 in Diabetic Retinopathy

“…Through deacetylation of various transcription factors (p53, p65, STAT3, etc. ), SIRT1 widely takes part in the regulation of inflammation, oxidative stress, autophagy, and cell apoptosis (Kitada et al, 2019;Sanz et al, 2019). Researchers believe that SIRT1 is a protective factor in DM and its complications (Potente et al, 2007;Boutant and Cantó, 2014;Collin et al, 2019;Myers et al, 2019).…”