Year-end Sale % OFF 
Abstract
Post-translational modifications of cardiac proteins could participate to left contractile dysfunction resulting in heart failure. Using a rat model of ischemic heart failure, we showed an accumulation of phosphorylated desmin leading to toxic aggregates in cardiomyocytes, but the cellular mechanisms are unknown. The same rat model was used to decipher the kinases involved in desmin phosphorylation and the proteolytic systems present in rat and human failing hearts. We used primary cultures of neonate rat cardiomyocytes for testing specific inhibitors of kinases and for characterizing the autophagic processes able to clear desmin aggregates. We found a significant increase of active PKCζ, no modulation of ubitiquitin-proteasome system, a defect in macroautophagy, and an activation of chaperone-mediated autophagy in heart failure rats. We validated in vitro that PKCζ inhibition induced a significant decrease of GSK3β and of soluble desmin. In vitro activation of ubiquitination of proteins and of chaperone-mediated autophagy is able to decrease soluble and insoluble forms of desmin in cardiomyocytes. These data demonstrate a novel signaling pathway implicating activation of PKCζ in desmin phosphorylation associated with a defect of proteolytic systems in ischemic heart failure, leading to desmin aggrephagy. Our in vitro data demonstrated that ubiquitination of proteins and chaperone-mediated autophagy are required for eliminating desmin aggregates with the contribution of its chaperone protein, α-crystallin Β-chain. Modulation of the kinases involved under pathological conditions may help preserving desmin intermediate filaments structure and thus protect the structural integrity of contractile apparatus of cardiomyocytes by limiting desmin aggregates formation.
Highlights
Left ventricular (LV) remodeling following myocardial infarction (MI) is one of the main causes of cardiac dysfunction leading to heart failure (HF) [1, 2]
We previously showed the presence of most of the phosphorylated desmin in the insoluble LV protein fraction of ischemic HF rats [4] suggesting that desmin phosphorylation, could promote the formation of desmin aggregates in failing heart, as already observed in a canine pacing model of desynchronous HF [10, 12] as well as in desminopathies
We selected four kinases by in silico screening of PKCζ on desmin phosphorylation and the modulation of (Fig. 1A), potentially involved in desmin phosphorylation, macroautophagy and chaperone-mediated autophagy (CMA) on clearance of soluble and insoluble calmodulin-dependent protein kinase II (CaMKII), Aurora B, protein kinase C (PKC) forms of desmin, we investigated these mechanisms in primary (ε and ζ isoforms), and Glycogen synthase kinase 3 (GSK3) (α and β isoforms)
Summary
Left ventricular (LV) remodeling following myocardial infarction (MI) is one of the main causes of cardiac dysfunction leading to heart failure (HF) [1, 2]. Several mechanisms implicated in LV remodeling such as infarct size, fibrosis, and apoptosis as well as alterations in contractile proteins and in intracellular calcium handling have been identified, the exact mechanisms underlying HF remain imperfectly known. Using an experimental rat model of ischemic HF and phosphoproteomic technologies, we previously identified increased levels of serine phosphorylated desmin in the LV of ischemic HF rats [3, 4]. Desmin is a 53kDa muscle-specific intermediate filament protein, which forms a three-dimensional scaffold around the myofibrillar Zdisk and interconnects the contractile apparatus to the cellular organelles [5]. The major effect of phosphorylation is the disassembly of desmin filaments [6] that impacts the solubilization of insoluble intermediate filaments [9]. Glycogen synthase kinase 3 (GSK3) β has been described to be involved in desmin phosphorylation [10], which was shown recently to induce calpain1-mediated muscle desmin depolymerization [11]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
