Cardiovascular stressors induce lysosomal dysfunction, sirtuin-1 depletion and premature senescence of vascular endothelium - Michael Goligorsky

Video Overview

Chronic cardiovascular and kidney diseases are associated with premature vascular senescence, which contributes to vasculopathy and accelerated progression of original malady. At least three independent pathways participate in this predilection to premature vascular/endothelial senescence, as will be discussed in the presentation.

  1. Frustrated autophagy pathway. This pathway can be initiated by each of the following non-traditional cardiovascular risk factors: asymmetric dimethylarginine (ADMA), advanced glycated end-products (AGEs), or a mimic of oxidative stress, hydrogen peroxide. Each leads to a rapid loss of integrity of the lysosomal membrane and collapse of lysosomal pH gradient. The latter results in impaired digestion of phagocytosed organelles or proteins within phagolysosomes, their engorgement, and accumulation of non-degraded materials destined for degradation.
  2. Sirtuin-1 depletion pathway. The same cardiovascular risk factors lead to depletion of endothelial sirtuin-1 and premature senescence of endothelial and endothelial progenitor cells. The mechanism of this depletion involves leakage of cathepsins, which directly degrade sirtuin-1.
  3. Putative amino acid-mediated mTOR pathway. Endothelial cell dysfunction induced by the above cardiovascular risk factors is associated with profound perturbations in cell metabolism. Proteomic analysis of dysfunctional endothelial cells reveales depletion of 2 mitochondrial enzymes of the Krebs cycle, namely, enoyl-CoA-hydratase and aconitase-2, consequently leading to a switch to the Warburg-type metabolism, normoxic glycolysis. Metabolomic profiling of microvasculature obtained from mice with chronic endothelial dysfunction reveales depletion of glutamine. It is possible that glutamine deficiency is responsible in part for the activation of mTOR, resulting in turn in further inhibition of autophagy and premature endothelial senescence.

Elucidation of these pathways of premature vascular senescence helped to design rational therapeutic strategies: 1) these pathways can be disrupted by antioxidants/peroxinitrite scavengers; 2) cathepsin inhibitors; and 3) supplementation with glutamine, resulting in the restoration of endothelial cell functions.