Hyperglycemic oxoaldehyde, glyoxal, causes barrier dysfunction, cytoskeletal alterations, and inhibition of angiogenesis in vascular endothelial cells: aminoguanidine protection.
Vascular endothelium is vulnerable to the attack of glucose-derived oxoaldehydes (glyoxal and methylglyoxal) during diabetes, through the formation of advanced glycation end products (AGEs). Although aminoguanidine (AG) has been shown to protect against the AGE-induced adverse effects, its protection against the glyoxal-induced alterations in vascular endothelial cells (ECs) such as cytotoxicity, barrier dysfunction, and inhibition of angiogenesis has not been reported and we investigated this in the bovine pulmonary artery ECs (BPAECs). The results showed that glyoxal (1-10 mM) significantly induced cytotoxicity and mitochondrial dysfunction in a dose- and time-dependent (4-12 h) fashion in ECs. Glyoxal was also observed to significantly inhibit EC proliferation. The study also revealed that glyoxal induced EC barrier dysfunction (loss of trans-endothelial electrical resistance), actin cytoskeletal rearrangement, and tight junction alterations in BPAECs. Furthermore, the results revealed that glyoxal significantly inhibited in vitro angiogenesis on the Matrigel. For the first time, this study demonstrated that AG significantly protected against the glyoxal-induced cytotoxicity, barrier dysfunction, cytoskeletal rearrangement, and inhibition of angiogenesis in BPAECs. Therefore, AG appears as a promising protective agent in the treatment of AGE-induced vascular endothelial alterations and dysfunction during diabetes, presumably by blocking the reactivity of the sugar-derived dicarbonyls such as glyoxal and preventing the formation of AGEs.
Sliman
Sean M
SM
Lipid Signaling and Lipidomics and Vasculotoxicity Laboratory, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH 43210, USA.
Eubank
Timothy D
TD
Kotha
Sainath R
SR
Kuppusamy
M Lakshmi
ML
Sherwani
Shariq I
SI
Butler
Elizabeth Susan O'Connor
ES
Kuppusamy
Periannan
P
Roy
Sashwati
S
Marsh
Clay B
CB
Stern
David M
DM
Parinandi
Narasimham L
NL
D000818:Animals; D002417:Cattle; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000187:drug effects* / Q000473:pathology; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D042783:Endothelial Cells / Q000648:ultrastructure; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D017127:Glycation End Products, Advanced; D006037:Glyoxal / Q000494:pharmacology*; D006146:Guanidines / Q000494:pharmacology* / Q000627:therapeutic use; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D020011:Protective Agents
D017127:Glycation End Products, Advanced; D006146:Guanidines; D020011:Protective Agents; D006037:Glyoxal; D019001:Nitric Oxide Synthase; C004479:pimagedine