Journal
MOLECULAR AND CELLULAR BIOCHEMISTRY
Volume 477, Issue 6, Pages 1803-1815Publisher
SPRINGER
DOI: 10.1007/s11010-022-04414-3
Keywords
Cytoskeleton; Heart; Integrin; Mouse; Sarcomeres; Paxillin
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Funding
- NIH [RO1 HL128468, PO1 HL062426, RO1 HL127691]
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In this study, the impact of chronic expression of cTnI-ND in transgenic mouse hearts was investigated. It was found that the modification of cTnI-ND in the sarcomere initiates changes in the phosphorylation signaling pathways, which may be involved in the chronic-adaptive response to stressors.
The cardiac isoform of troponin I has a unique N-terminal extension (similar to 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 similar to 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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