Abstract
We hypothesized that reperfused myocardial infarction (RMI) induces post-translational modifications (PTMs) of the metabolic enzyme mitochondrial ATP synthase D-chain (ATP/D) which are reversed by the angiotensin II type 1 receptor (AT 1 R) blocker valsartan. We applied a pharmaco-proteomics approach to detect regional differences in PTMs of ATP/D in ischemic (IZ) and non-ischemic (NIZ) zones of hearts subjected to in vivo RMI (90 min left anterior descending coronary occlusion; 120 min reperfusion) in dogs randomized to placebo or valsartan. We measured hemodynamics and left ventricular (LV) function (2D-Echocardiogram/ Doppler) and identified/analyzed ATP/D using 2D electrophoresis, PD Quest, and in-gel trypsin digestion of protein spots (Fig. A ) followed by mass spectrometry, and FindMod tool for finding potential PTMs. Compared to sham, RMI induced ischemic injury and systolic and diastolic dysfunction in the placebo group and these were attenuated by valsartan. Compared to the NIZ, RMI increased ATP/D in the IZ (nearly 2-fold) and this was normalized by valsartan (Fig. B ). Importantly, RMI increased hydroxylation of ATP/D, S-nitrosylation of cysteine-100, nitration of tyrosine-80 and -225, and hydroxylation of lysine-182 followed by its myristoylation (Fig. C ). Valsartan reduced ATP/D hydroxylation, abolished the PTMs including lysine myristoylation in the IZ, and additionally triggered phosphorylation of serine-76 in both the IZ and NIZ. Valsartan-induced cardioprotection is associated with reversal of PTMs of ATP/D during RMI. This new pleiotropic effect of AT 1 R blockade suggests that PTMs may represent a novel therapeutic target after RMI.
Published Version
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