Protein kinase A-dependent translocation of Hsp90 alpha impairs endothelial nitric-oxide synthase activity in high glucose and diabetes.
Diabetes mellitus (DM) and high glucose (HG) are known to reduce the bioavailability of nitric oxide (NO) by modulating endothelial nitric-oxide synthase (eNOS) activity. eNOS is regulated by several mechanisms including its interaction with heat shock protein (Hsp) 90. We previously discovered that DM in vivo and HG in vitro induced the translocation of Hsp90alpha to the outside of aortic endothelial cells. In this report we tested the hypothesis that translocation of Hsp90alpha is responsible for the decline in NO production observed in HG-treated cells. We found that HG increased phosphorylation of Hsp90alpha in a cAMP-dependent protein kinase A-dependent manner, and that this event was required for translocation of Hsp90alpha in porcine aortic endothelial cells. Furthermore, preventing translocation of Hsp90alpha protected from the HG-induced decline in eNOS.Hsp90alpha complex and NO production. Notably, DM increased phosphorylation of Hsp90alpha and reduced its association with eNOS in the aortic endothelium of diabetic rats. These studies suggest that translocation of Hsp90alpha is a novel mechanism by which HG and DM impair eNOS activity and thereby reduce NO production.
Lei
Hetian
H
Schepens Eye Research Institute and Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts 02114.
Venkatakrishnan
Annapurna
A
Schepens Eye Research Institute and Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts 02114.
Yu
Soyoung
S
Schepens Eye Research Institute and Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts 02114.
Kazlauskas
Andrius
A
Schepens Eye Research Institute and Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts 02114. Electronic address: ak@eri.harvard.edu.
D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology* / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D006943:Hyperglycemia / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D051379:Mice; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010766:Phosphorylation; D021381:Protein Transport / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013552:Swine; D015027:Zebrafish
D018841:HSP90 Heat-Shock Proteins; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D017868:Cyclic AMP-Dependent Protein Kinases