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Valsartan reverses post‐translational modifications of the δ‐subunit of ATP synthase during in vivo canine reperfused myocardial infarction
Author(s) -
Sawicki Grzegorz,
Jugdutt Bodh I.
Publication year - 2007
Publication title -
proteomics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.26
H-Index - 167
eISSN - 1615-9861
pISSN - 1615-9853
DOI - 10.1002/pmic.200601022
Subject(s) - valsartan , chemistry , cardioprotection , atp synthase , s nitrosylation , phosphorylation , pharmacology , nitric oxide , biochemistry , cysteine , biology , myocardial infarction , medicine , enzyme , organic chemistry , blood pressure
To determine whether reperfused myocardial infarction (RMI) induces PTM of the δ‐subunit of the mitochondrial metabolic enzyme ATP synthase (ATP/δ) 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/δ 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/δ followed by its myristoylation. Importantly, valsartan abolished these modifications of ATP/δ 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/δ 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/δ 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.