Truncation of the N-terminus of cardiac troponin I initiates adaptive remodeling of the myocardial proteosome via phosphorylation of mechano-sensitive signaling pathways - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Molecular and Cellular Biochemistry Année : 2022

Truncation of the N-terminus of cardiac troponin I initiates adaptive remodeling of the myocardial proteosome via phosphorylation of mechano-sensitive signaling pathways

Résumé

The cardiac isoform of troponin I has a unique N-terminal extension (~ 1-30 amino acids), which contributes to the modulation of cardiac contraction and relaxation. Hearts of various species including humans produce a truncated variant of cardiac troponin I (cTnI-ND) deleting the first ~ 30 amino acids as an adaption in pathophysiological conditions. In this study, we investigated the impact of cTnI-ND chronic expression in transgenic mouse hearts compared to wildtype (WT) controls (biological n = 8 in each group). We aimed to determine the global phosphorylation effects of cTnI-ND on the cardiac proteome, thereby determining the signaling pathways that have an impact on cardiac function. The samples were digested and isobarically labeled and equally mixed for relative quantification via nanoLC-MS/MS. The peptides were then enriched for phospho-peptides and bioinformatic analysis was done with Ingenuity Pathway Analysis (IPA). We found approximately 77% replacement of the endogenous intact cTnI with cTnI-ND in the transgenic mouse hearts with 1674 phospho-proteins and 2971 non-modified proteins. There were 73 significantly altered phospho-proteins; bioinformatic analysis identified the top canonical pathways as associated with integrin, protein kinase A, RhoA, and actin cytoskeleton signaling. Among the 73 phospho-proteins compared to controls cTnI-ND hearts demonstrated a significant decrease in paxillin and YAP1, which are known to play a role in cell mechano-sensing pathways. Our data indicate that cTnI-ND modifications in the sarcomere are sufficient to initiate changes in the phospho-signaling profile that may underly the chronic-adaptive response associated with cTnI cleavage in response to stressors by modifying mechano-sensitive signaling pathways.
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Dates et versions

hal-03621298 , version 1 (17-11-2022)

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Chad Warren, Monika Halas, Paul Goldspink, Han-Zhong Feng, Anthony Herren, et al.. Truncation of the N-terminus of cardiac troponin I initiates adaptive remodeling of the myocardial proteosome via phosphorylation of mechano-sensitive signaling pathways. Molecular and Cellular Biochemistry, In press, ⟨10.1007/s11010-022-04414-3⟩. ⟨hal-03621298⟩
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