Irreversible oxidative post-translational modifications in heart disease

Abstract

Introduction: Development of specific biomarkers aiding early diagnosis of heart failure is an ongoing challenge. Biomarkers commonly used in clinical routine usually act as readouts of an already existing acute condition rather than disease initiation. Functional decline of cardiac muscle is greatly aggravated by increased oxidative stress and damage of proteins. Oxidative post-translational modifications occur already at early stages of tissue damage and are thus regarded as potential up-coming disease markers. Areas covered: Clinical practice regarding commonly used biomarkers for heart disease is briefly summarized. The types of oxidative post-translational modification in cardiac pathologies are discussed with a special focus on available quantitative techniques and characteristics of individual modifications with regard to their stability and analytical accessibility. As irreversible oxidative modifications trigger protein degradation pathways or cause protein aggregation, both influencing biomarker abundance, a chapter is dedicated to their regulation in the heart.

Keywords: Heart failure; oxidative stress; post-translational modifications; protein aggregation; protein degradation.

Figure 1.

Most common oxPTMs. Blue boxes symbolize amino acids, green boxes represent reversible modifications and grey boxes irreversible ones.

Figure 2.

Overview of Cys modifications. Marked in red are irreversible oxPTMs. Grey dotted line: limited reversibility of sulfinic acid, RNOS – reactive oxygen and nitrogen species, RNS – reactive nitrogen species, GSH – glutathione.

Figure 3.

Effects of reversible and irreversible oxPTMs on protein function and stability. Reversible oxPTMs can either modulate protein function, get removed to restore native protein or induce degradation of damaged proteins, while irreversible oxPTMs usually cause loss of protein function and can either increase degradation or cause aggregation and accumulation of oxidized proteins due to inhibition of proteasomal activity.

Figure 4.

Chemoselective tagging of sulfinic acid residues employing electron-deficient diazenes [56].

Figure 5.

Selected amino acid carbonylation reactions. Amino acids (Lys (1), Pro (2), Arg (3), Cys (4), His (5)) can either react directly with RNOS (black arrows, 6, 8, 12) or with lipid peroxidation products (LPP, red arrows, 7, 9, 10, 11). Conjugates with malondialdehyde are depicted here as an exemplary LPP but many others including 4-hydroxynonenal and glycolysis side products such as glyoxal and methylglyoxal have been reported [53,71]. LPP can either react via Schiff base formation (7, 9) or by Michael-addition (10, 11). The reactive carbonyl groups can subsequently react with other amino groups of intra or intermolecular origin leading to a vast variety of different end products (13–16). Alternatively, hydrolysis, oxidation or enzymatic detoxification, e.g. via aldehyde dehydrogenases can yield stable end products with low reactivity (17–19).