Accelerated atherosclerosis and premature aging of the cardiovascular system in patients with diabetes mellitus and metabolic syndrome have acquired epidemic proportions. Our previous studies of endothelial cells subjected to a microenvironment emulating the diabetic milieu revealed accelerated development of cell senescence. Based on the observations that the expression of nitrotyrosine-modified proteins was enhanced in the prematurely senescent cells and peroxynitrite treatment of intact cells led to premature senescence, we treated endothelial cells with a bona fide peroxynitrite scavenger/antioxidant ebselen. Such a treatment was associated with the prevention and reversal of premature senescence. These findings prompted us to investigate the molecular mechanism(s) of premature cell senescence, effects of ebselen on premature endothelial cell senescence in a model of metabolic syndrome - Zucker diabetic rats, and examine the development of vasculopathy in these animals. We hypothesize that oxidative stress/peroxynitrite-induced lysosomal dysfunction initiates endothelial cell senescence and accumulation of gangliosides, a molecular switch from senescence to apoptosis- events underpinning the progression of vasculopathy. In vitro and in vivo studies employing image analysis and fluorescence intravital microscopy, biochemical techniques to detect leakage of lysosomal and mitochondria! proteins as well as accumulation of gangliosides, and quntitative analysis of the markers of cell cycle are designed to investigate molecular and cellular mechanisms of premature senescence and apoptosis. In vivo studies of the Zucker diabetic fat rat treated with ebselen will be conducted to examine the possibility of preventing and reversing macro- and micro-vasculopathy (nephropathy) in this syndrome. The investigations may shed light on mechanisms of premature senescence of endothelial cells, role of peroxynitrite in initiating it, and potential therapeutic efficacy of peroxynitrite scavenging in amelioration of vasculopathy.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Rys-Sikora, Krystyna E
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
New York Medical College
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Matsumoto, Kei; Xavier, Sandhya; Chen, Jun et al. (2017) Instructive Role of the Microenvironment in Preventing Renal Fibrosis. Stem Cells Transl Med 6:992-1005
Song, J W; Zullo, J A; Liveris, D et al. (2017) Therapeutic Restoration of Endothelial Glycocalyx in Sepsis. J Pharmacol Exp Ther 361:115-121
Lipphardt, Mark; Song, Jong W; Matsumoto, Kei et al. (2017) The third path of tubulointerstitial fibrosis: aberrant endothelial secretome. Kidney Int 92:558-568
Kida, Yujiro; Zullo, Joseph A; Goligorsky, Michael S (2016) Endothelial sirtuin 1 inactivation enhances capillary rarefaction and fibrosis following kidney injury through Notch activation. Biochem Biophys Res Commun 478:1074-9
Zullo, Joseph A; Fan, Jie; Azar, Tala T et al. (2016) Exocytosis of Endothelial Lysosome-Related Organelles Hair-Triggers a Patchy Loss of Glycocalyx at the Onset of Sepsis. Am J Pathol 186:248-58
Lin, Chi Hua Sarah; Chen, Jun; Zhang, Zhongtao et al. (2016) Endostatin and transglutaminase 2 are involved inĀ fibrosis of the aging kidney. Kidney Int 89:1281-92
Kida, Yujiro; Goligorsky, Michael S (2016) Sirtuins, Cell Senescence, and Vascular Aging. Can J Cardiol 32:634-41
Goligorsky, M S; Hirschi, K (2016) Stress-Induced Premature Senescence of Endothelial and Endothelial Progenitor Cells. Adv Pharmacol 77:281-306
Zullo, Joseph A; Nadel, Ellen P; Rabadi, May M et al. (2015) The Secretome of Hydrogel-Coembedded Endothelial Progenitor Cells and Mesenchymal Stem Cells Instructs Macrophage Polarization in Endotoxemia. Stem Cells Transl Med 4:852-61
Zullo, Joseph; Matsumoto, Kei; Xavier, Sandhya et al. (2015) The cell secretome, a mediator of cell-to-cell communication. Prostaglandins Other Lipid Mediat 120:17-20

Showing the most recent 10 out of 98 publications