title: Diabetes triggers a PARP1 mediated death pathway in the heart through participation of FoxO1.
abstract: Cardiomyocyte cell death is a major contributing factor for diabetic cardiomyopathy, and multiple mechanisms have been proposed for its development. We hypothesized that following diabetes, an increased nuclear presence of the Forkhead transcription factor, FoxO1, could turn on cardiac cell death through mediation of nitrosative stress. Streptozotocin (100 mg/kg) was used to induce irreversible hyperglycemia in Wistar rats, and heart tissues and blood samples extracted starting from 1 to 4 days. Diazoxide (100 mg/kg), which produced acute reversible hyperglycemia, were followed for up to 12 h. In both animal models of hyperglycemia, attenuation of survival signals was accompanied by increased nuclear FoxO1. This was accompanied by a simultaneous increase in iNOS expression and iNOS induced protein nitrosylation of GAPDH, increased GAPDH binding to Siah1 and facilitated nuclear translocation of the complex. Even though caspase-3 was cleaved during diabetes, its nitrosylation modification affected its ability to inactivate PARP. As a result, there was PARP activation followed by nuclear compartmentalization of AIF, and increased phosphatidyl serine externalization. Our data suggests a role for FoxO1 mediated iNOS induced S-nitrosylation of target proteins like GAPDH and caspase-3 in initiating cardiac cell death following hyperglycemia, and could explain the impact of glycemic control in preventing cardiovascular disease in patients with diabetes.
authors.affiliation: The University of British Columbia, 2146 East Mall, Vancouver, BC, Canada V6T 1Z3.
authors.forename: Prasanth
authors.initials: P
authors.lastname: Puthanveetil
authors.forename: Dahai
authors.initials: D
authors.lastname: Zhang
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.forename: Andrea
authors.initials: A
authors.lastname: Wan
authors.forename: Ashraf
authors.initials: A
authors.lastname: Abrahani
authors.forename: Brian
authors.initials: B
authors.lastname: Rodrigues
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D017209:Apoptosis; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D001786:Blood Glucose; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D003981:Diazoxide; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005947:Glucose / Q000502:physiology; D006943:Hyperglycemia / Q000139:chemically induced / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D026361:Reactive Nitrogen Species / Q000097:blood / Q000378:metabolism; D013312:Stress, Physiological; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D000071161:Forkhead Box Protein O1
chemical_list: D051033:Apoptosis Inducing Factor; D001786:Blood Glucose; D003981:Diazoxide; D051858:Forkhead Transcription Factors; D005947:Glucose; D009419:Nerve Tissue Proteins; D052247:Nitric Oxide Synthase Type II; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D026361:Reactive Nitrogen Species; D014443:Tyrosine; C494831:Aifm1 protein, rat; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1; C002744:3-nitrotyrosine; C496318:Nos2 protein, rat; C499322:Parp1 protein, rat