Decreased tetrahydrobiopterin and disrupted association of Hsp90 with eNOS by hyperglycemia impair myocardial ischemic preconditioning. Am J Physiol Heart Circ Physiol 2011 Nov;301(5):H2130-9
Date
09/13/2011Pubmed ID
21908789Pubmed Central ID
PMC3213977DOI
10.1152/ajpheart.01078.2010Scopus ID
2-s2.0-80355129947 (requires institutional sign-in at Scopus site) 34 CitationsAbstract
Cardioprotection by ischemic preconditioning (IPC) is impaired during hyperglycemia, but the mechanisms underlying this phenomenon are poorly understood. This study investigated the role of hyperglycemia to adversely modulate tetrahydrobiopterin (BH(4)) and heat shock protein 90 (Hsp90) during cardioprotection by IPC. Rabbits or mice underwent 30 min of coronary occlusion followed by reperfusion with or without IPC in the presence or absence of hyperglycemia. IPC significantly (P < 0.05) decreased myocardial infarct size (46 ± 1 to 19 ± 2% of the area at risk in control and IPC rabbits, respectively) and increased BH(4) concentrations (HPLC; 7.6 ± 0.2 to 10.2 ± 0.3 pmol/mg protein, respectively), Hsp90-endothelial nitric oxide synthase (eNOS) association (coimmunoprecipitation and Western blotting in mice; 4.0 ± 0.3 to 5.4 ± 0.1, respectively), and the ratio of phosphorylated eNOS/total eNOS. These beneficial actions of IPC on infarct size, BH(4), Hsp90/eNOS, and phosphorylated eNOS were eliminated by hyperglycemia. Pretreatment of animals with the Hsp90 inhibitor geldanamycin (0.6 mg/kg) or the BH(4) synthesis inhibitor diamino-6-hydroxypyrimidine (1.0 g/kg) also eliminated cardioprotection produced by IPC. In contrast, the BH(4) precursor sepiapterin (2 mg/kg iv) restored the beneficial effects of IPC on myocardial BH(4) concentrations, eNOS dimerization, and infarct size during hyperglycemia. A-23871 increased Hsp90-eNOS association (0.33 ± 0.06 to 0.59 ± 0.3) and nitric oxide production (184 ± 17%) in human coronary artery endothelial cells cultured in normal (5.5 mM) but not high (20 mM) glucose media. These data indicate that hyperglycemia eliminates protection by IPC via decreases in myocardial BH(4) concentration and disruption of the association of Hsp90 with eNOS. The results suggest that eNOS dysregulation may be a central mechanism of impaired cardioprotection during hyperglycemia.
Author List
Vladic N, Ge ZD, Leucker T, Brzezinska AK, Du JH, Shi Y, Warltier DC, Pratt PF Jr, Kersten JRMESH terms used to index this publication - Major topics in bold
AnimalsBenzoquinones
Blood Glucose
Blotting, Western
Cells, Cultured
Coronary Occlusion
Disease Models, Animal
Endothelial Cells
HSP90 Heat-Shock Proteins
Hyperglycemia
Immunoprecipitation
Ischemic Preconditioning, Myocardial
Lactams, Macrocyclic
Male
Mice
Mice, Inbred C57BL
Myocardial Infarction
Myocardial Reperfusion Injury
Myocardium
Nitric Oxide
Nitric Oxide Synthase Type III
Phosphorylation
Protein Multimerization
Pterins
Rabbits
Time Factors