Modulation of cell injury and survival by high glucose and advancing age

Old age is associated with a higher prevalence of cardiovascular disease and diabetes mellitus. Vascular smooth muscle cells (VSMC) play a role in the pathogenesis of vascular diseases, often a complication of diabetes mellitus. We examined in explanted aortic VSMC from young vs. older rats glucose-related activation of nuclear factor kappaB (NF-kappaB), a transcription factor induced by many oxidants. Data demonstrate that old age is associated with enhanced NF-kappaB activity in unstimulated VSMC that is further increased after exposure to high glucose medium. Furthermore, VSMC from old animals exhibit increased levels of protein carbonyls, an indicator of oxidative stress, and less apoptosis in response to glucose than VSMC isolated from young animals. These changes are accompanied by increased expression of NF-kappaB-related genes, gamma-glutamylcysteine synthetase, inhibitor of apoptosis protein-1 (IAP-1), and inducible nitric oxide synthase (iNOS). Results suggest that high glucose, a putative oxidative stress, causes apoptosis in VSMC from young animals and is associated with greater induction of NF-kappaB in VSMC from older animals. Increases in IAP-1 and decreased apoptosis implicate NF-kappaB as a survival factor in VSMC.