Implications of S-glutathionylation of sarcomere proteins in cardiac disorders, therapies, and diagnosis

Abstract

The discovery that cardiac sarcomere proteins are substrates for S-glutathionylation and that this post-translational modification correlates strongly with diastolic dysfunction led to new concepts regarding how levels of oxidative stress affect the heartbeat. Major sarcomere proteins for which there is evidence of S-glutathionylation include cardiac myosin binding protein C (cMyBP-C), actin, cardiac troponin I (cTnI) and titin. Our hypothesis is that these S-glutathionylated proteins are significant factors in acquired and familial disorders of the heart; and, when released into the serum, provide novel biomarkers. We consider the molecular mechanisms for these effects in the context of recent revelations of how these proteins control cardiac dynamics in close collaboration with Ca2+ fluxes. These revelations were made using powerful approaches and technologies that were focused on thin filaments, thick filaments, and titin filaments. Here we integrate their regulatory processes in the sarcomere as modulated mainly by neuro-humoral control of phosphorylation inasmuch evidence indicates that S-glutathionylation and protein phosphorylation, promoting increased dynamics and modifying the Frank-Starling relation, may be mutually exclusive. Earlier studies demonstrated that in addition to cTnI as a well-established biomarker for cardiac disorders, serum levels of cMyBP-C are also a biomarker for cardiac disorders. We describe recent studies approaching the question of whether serum levels of S-glutathionylated-cMyBP-C could be employed as an important clinical tool in patient stratification, early diagnosis in at risk patients before HFpEF, determination of progression, effectiveness of therapeutic approaches, and as a guide in developing future therapies.

Bringing into focus the central domains C3-C6 of myosin binding protein C

“…Circulating levels of S-glutathionylated cardiac MyBPC were positively correlated with diastolic dysfunction in humans and significantly increased in the animal models of diastolic dysfunction compared to disease-free controls ( Zhou et al, 2022a ). This implicates the clinical relevance of the central domains of MyBPC and its potential for detecting the early stages of heart failure with preserved ejection fraction (HFpEF) and disease stratification ( Rosas and Solaro, 2022 ).…”

Hypertrophic cardiomyopathy in MYBPC3 carriers in aging

“…Novel therapeutic strategies, such as direct activation [ 212 , 213 ] and/or inactivation [ 214 ] of myosin, are needed to ameliorate the side effects associated with current pharmacological therapies. -AR stimulation activates protein kinase A, which phosphorylates sarcomeric myofilament proteins, including cMyBP-C. cMyBP-C undergoes other post-translational modifications (PTM), including ubiquitination, SUMOylation, O-GlcNAcylation, methylation, carbonylation, and acetylation [ 215 , 216 ] . However, a systematic study is required to link the PTM of cMyBP-C to the development of HCM [ 217 – 219 ] .…”

The role of endosarcomeric cytoskeleton proteins in the mechanisms of left ventricular diastolic dysfunction: focus on titin

“…Несмотря на то, что в настоящее время достаточно много известно о механизмах ДД ЛЖ, немало важных вопросов, касающихся патофизиологии диастолы, еще ожидают своего решения. В частности, нуждается в уточнении роль патологии белков эндосаркомерного скелета в ухудшении так называемых активных (релаксация миокарда желудочка и тесно связанный с ней в здоровом сердце атриовентрикулярный градиент давления в начале диастолы) и пассивных (миокардиальная жесткость) характеристик диастолы [22][23][24][25][26].…”