Non-histone lysine acetylated proteins in heart failure

Abstract

Both histone-acetylations and histone deacetylases have been shown to play a key role in cardiac remodeling. Recently, it has become abundantly clear that many non-histone proteins are modified by post-translational lysine acetylations and that these acetylations regulate protein activity, conformation, and binding. In the present study, non-histone acetylated proteins associated with heart failure were identified. Global screening for lysine acetylated proteins was performed using 2-dimensional gel electrophoresis coupled with immunoblotting with a primary monoclonal anti-acetyl-lysine antibody. Lysine acetylated proteins were compared in two rodent models of hypertensive heart failure, the Dahl salt-sensitive (SS) and spontaneously hypertensive heart failure prone (SHHF) rats with those in corresponding controls, i.e., the Dahl salt-resistant (SR) and W (W) rat strains, respectively. Forty-one and 66 acetylated proteins were detected in SS and SHHF failing hearts, respectively, but either not detected or detected with less abundance in corresponding control hearts. Twelve of these acetylated proteins were common to both models of heart failure. These were identified using matrix-assisted laser desorption/ionization time of flight (MALDI-TOF/TOF) mass spectrometry followed by Mascot Analysis and included mitochondrial enzymes: ATP synthase, long-chain acyl-CoA dehydrogenase, creatine kinase, malate dehydrogenase, and pyruvate dehydrogenase. The abundance of NAD-dependent deacetylase sirtuin-3 (Sirt3), a mitochondrial deacetylase was reduced in SS and SHHF failing hearts. This is the first description of non-histone protein acetylations associated with heart failure and raises the prospect that acetylations of mitochondrial proteins linked to reduced Sirt3 mediate, in part, metabolic changes in heart failure.1

Moonlighting cell surface GAPDH recruits Apo Transferrin to effect iron egress from mammalian cells

“…Our LC-MS/MS results demonstrate that GAPDH recruited upon iron loading lacks phosphorylation and acetylation and also has a lower abundance of several PTMs, including oxidation, dimethylation and nitrosylation in comparison to GAPDH recruited upon iron depletion. These modifications are well known for their ability to shift the isoelectric point of proteins as observed by us in this study, as well as by numerous other workers previously (Choudhary et al, 2000;Grillon et al, 2012;Kuyumcu-Martinez et al, 2007;Madian et al, 2012;Park et al, 1988;Zhang et al, 2011). The presence of numerous PTMs in GAPDH has been well established in earlier reports (Seidler, 2013;Seo et al, 2008).…”

SIRT3 deficiency impairs mitochondrial and contractile function in the heart

“…Impairment in mitochondrial energetics is a hallmark of the failing heart; the underlying mechanisms of which remain incompletely understood, but may include oxidative stress and impairment in mitochondrial biogenic signaling [12,30]. Recent studies showed that expression of SIRT3 is decreased in the failing rat heart, accompanied by increased acetylation of mitochondrial enzymes such as ATP synthase, long-chain acyl-CoA dehydrogenase, malate dehydrogenase, and pyruvate dehydrogenase [17,38]. In addition, activity of poly(adenosine diphosphate-ribose) polymerase 1 (PARP-1) is increased in the failing heart, whereas expression of nicotinamide phosphoribosyltransferase (Nampt) is decreased, both resulting in myocardial NAD ?…”

“…Thus, when extrapolating the metabolic and functional data of the current study and the data available from the literature, it is tempting to speculate that mitochondrial NAD ? depletion and/or decreased SIRT3 expression may impair SIRT3 activity and thereby contribute to impairment in mitochondrial energetics and contractile function in failing hearts [17,51].…”

“…Studies in failing hearts showed decreased expression of SIRT3, evidence of myocardial NAD ? depletion, and increased acetylation of mitochondrial enzymes such as ATP synthase, LCAD, malate dehydrogenase, and pyruvate dehydrogenase, suggesting a potential contribution of decreased SIRT3 activity to impaired mitochondrial energetics in the failing heart [12,17,21,37,38,40,41,51,54]. However, while SIRT3 has been shown to regulate mitochondrial energy metabolism in various extracardiac tissues, comprehensive experimental evidence of SIRT3-mediated regulation of myocardial energetics is lacking to date.…”

Mitochondrial sirtuins in the heart

“…during decompensated hypertrophy and heart failure [45]. Indeed, lysine acetylation is increased in human failing hearts, even accompanied by reduced SIRT3 expression [45,46]. Another attractive hypothesis for decreased NAD ?…”