The role of post‐translational modifications in acute and chronic cardiovascular disease

Abstract

Cardiovascular disease (CVD) in one of the leading causes of mortality and morbidity worldwide, accounting for both primary diseases of the heart and vasculature and arising as a co-morbidity with numerous pathologies, including type 2 diabetes mellitus (T2DM). There has been significant emphasis on the role of the genome in CVD, aiding in the definition of 'at-risk' patients. The extent of disease penetrance however, can be influenced by environmental factors that are not detectable by investigating the genome alone. By targeting the transcriptome in response to CVD, the interplay between genome and environment is more apparent, however this implies the level of protein expression without reference to proteolytic turnover, or potentially more importantly, without defining the role of PTMs in the development of disease. Here, we discuss the role of both brief and irreversible PTMs in the setting of myocardial ischemia/reperfusion injury. Key proteins involved in calcium regulation have been observed as differentially modified by phosphorylation/O-GlcNAcylation or phosphorylation/redox modifications, with the level of interplay dependent on the physiological or pathophysiological state. The ability to modify crucial sites to produce the desired functional output is modulated by the presence of other PTMs as exemplified in the T2DM heart, where hyperglycemia results in aberrant O-GlcNAcylation and advanced glycation end products. By using the signalling events predicted to be critical to post-conditioning, an intervention with great promise for the cardioprotection of the ischemia/reperfusion injured heart, as an example, we discuss the level of PTMs and their interplay. The inability of post-conditioning to protect the diabetic heart may be regulated by aberrant PTMs influencing those sites necessary for protection.

HDAC1 localizes to the mitochondria of cardiac myocytes and contributes to early cardiac reperfusion injury

“…Here, we identify another mitochondrial deacetylase, HDAC1, which plays a critical role in regulating the metabolic response of the heart to injury. Given recent work demonstrating perturbations of the mitochondrial acetylome in heart failure [52] and other cardiac pathologies [53], the discovery of HDAC1 as a mitochondrial deacetylase in cardiac myocytes opens up exciting new opportunities in both dissecting the mitochondrial elements of the pathogenesis of these diseases and designing new cardiovascular therapeutics.…”

Transformative Impact of Proteomics on Cardiovascular Health and Disease

“…74 Abundant examples in the literature are available, including a special issue on cardiovascular disease that focused on clinical and translational proteomics. [75][76][77][78][79][80][81][82][83][84][85][86][87] One specific example is activity-based protein profiling with proteomic techniques, which is currently being used to annotate the enzymatic proteome and uses chemical probes that target large groups of enzymes that have similar active-site features. 88 Contributing to the posttranscriptional complexity of the proteome are alternative splicing and isoform variants, often with extensive peptide redundancies, that are not easily addressed by standard rules of parsimony when acquired in the context of multidimensional quantitative proteomic studies.…”

Measuring proteomes with long strings: A new, unconstrained paradigm in mass spectrum interpretation

“…Our strategy contrasts with prior approaches that extract many (>100) short sequence fragments (“tags”) from each input MS/MS spectrum to restrict protein candidates 37–39 . Although they consider fewer peptides per mass spectrum than conventional database search algorithms, they are subject to similar speed limitations if they consider large numbers of amino acid modifications and variants.…”