Inhibition of Endothelial p53 Improves Metabolic Abnormalities Related to Dietary Obesity

Abstract

Accumulating evidence has suggested a role for p53 activation in various age-associated conditions. Here, we identified a crucial role of endothelial p53 activation in the regulation of glucose homeostasis. Endothelial expression of p53 was markedly upregulated when mice were fed a high-calorie diet. Disruption of endothelial p53 activation improved dietary inactivation of endothelial nitric oxide synthase that upregulated the expression of peroxisome proliferator-activated receptor-γ coactivator-1α in skeletal muscle, thereby increasing mitochondrial biogenesis and oxygen consumption. Mice with endothelial cell-specific p53 deficiency fed a high-calorie diet showed improvement of insulin sensitivity and less fat accumulation, compared with control littermates. Conversely, upregulation of endothelial p53 caused metabolic abnormalities. These results indicate that inhibition of endothelial p53 could be a novel therapeutic target to block the vicious cycle of cardiovascular and metabolic abnormalities associated with obesity.

Obesity and related consequences to ageing

“…Upregulation of p53 gene activity in AT caused an inflammatory response and led to insulin resistance, while its inhibition in AT significantly decreased the expression of pro-inflammatory cytokines and improved insulin resistance in mice with type 2 diabetes-like disease (Minamino et al 2009). Furthermore, recent studies on mice skeletal muscle indicate that endothelial p53 regulates glucose metabolism by modulating mitochondrial biogenesis and glucose uptake in this tissue (Yokoyama et al 2014). This work demonstrated the existence of a mechanism for a cycle in which upregulation of endothelial p53 induces metabolic abnormalities that in turn promote cardiovascular dysfunction (Yokoyama et al 2014).…”

“…Furthermore, recent studies on mice skeletal muscle indicate that endothelial p53 regulates glucose metabolism by modulating mitochondrial biogenesis and glucose uptake in this tissue (Yokoyama et al 2014). This work demonstrated the existence of a mechanism for a cycle in which upregulation of endothelial p53 induces metabolic abnormalities that in turn promote cardiovascular dysfunction (Yokoyama et al 2014).…”

“…Inhibition of endothelial p53 has been proposed as a novel therapeutic strategy for blocking the development of insulin resistance in obese patients (Yokoyama et al 2014) as well as postponing skeletal muscle ageingrelated processes (Edwards et al 2007). …”

The Pulse of Asia 2017 Taipei. May 5-6, 2017, Taipei, Taiwan: Abstracts

“…Factors which contribute to optimal function have been emphasised by Michael Taylor in his observational and modelling studies, and are summarised in "McDonald's Blood Flow in Arteries" [1]. The system of branching pipes, with proximal distensibility and distal stiffness limits the volume of blood which is held in arteries while the junction of conduit arteries with resistance arterioles at the distal end creates wave reflection which excludes flow pulsations from the arterioles and capillaries while creating a pressure wave which moves back to the heart with such timing that its foot corresponds to aortic valve closure, so maintaining coronary flow without increasing aortic or Left Ventricular (LV) systolic pressure.…”

“…All have a predominant effect in reducing wave reflection while maintaining peripheral resistance and perfusion of vital organs [1,3].…”