Valsartan reverses post-translational modifications of the delta-subunit of ATP synthase during in vivo canine reperfused myocardial infarction.
To determine whether reperfused myocardial infarction (RMI) induces PTM of the delta-subunit of the mitochondrial metabolic enzyme ATP synthase (ATP/delta) in the ischemic zone (IZ) and whether this can be reversed by the angiotensin II type 1 receptor (AT(1)R) blocker valsartan, we applied a pharmaco-proteomics approach in canine RMI hearts with or without valsartan pretreatment. Using the 2-DE technique, we identified differential regional expression of ATP/delta in the IZ compared to the non-ischemic zone (NIZ), with an approximately 2-fold increase in the IZ that was normalized by valsartan. Furthermore in the IZ, RMI triggered S-nitrosylation of cysteine-100, nitration of the two tyrosines 88 and 225, and hydroxylation of lysine-182 in ATP/delta followed by its myristoylation. Importantly, valsartan abolished these modifications of ATP/delta in the IZ, triggered phosphorylation of serine-76 in both the IZ and NIZ, and decreased necrosis, apoptosis, left ventricular dysfunction and remodeling. Thus, AT(1)R-blocker-induced cardioprotection during RMI is associated with phosphorylation of ATP/delta and inhibition of nitric oxide-related chemical modifications such as S-nitrosylation, nitration and hydroxylation. Targeting specific PTMs during RMI, such as those of ATP/delta with AT(1)R blockade, might be a potentially powerful novel therapeutic approach. However, the identification of S-nitrosylation was putative and requires MS/MS verification.
Sawicki
Grzegorz
G
Department of Pharmacology, University of Saskatchewan, Saskatoon, Canada.
Jugdutt
Bodh I
BI
D000596:Amino Acids / Q000378:metabolism; D057912:Angiotensin II Type 2 Receptor Blockers; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004285:Dogs; D025261:Mitochondrial Proton-Translocating ATPases / Q000378:metabolism*; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000503:physiopathology; D009336:Necrosis / Q000188:drug therapy; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000502:physiology*; D021122:Protein Subunits / Q000378:metabolism*; D040901:Proteomics; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism; D013777:Tetrazoles / Q000627:therapeutic use*; D014633:Valine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000068756:Valsartan; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology
D000596:Amino Acids; D057912:Angiotensin II Type 2 Receptor Blockers; D021122:Protein Subunits; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles; D000068756:Valsartan; D025261:Mitochondrial Proton-Translocating ATPases; D014633:Valine