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KLHL40- mediated regulation of Cardiac sarcomeric integrity and Function post- myocardial infarction

molecular-biology
cardiology
evidence-based-medicine
pathology
medical-genetics

Abstract

Background: Cardiac sarcomeric remodeling after myocardial infarction (MI) plays a pivotal role in post-injury cardiac dysfunction, yet the molecular mechanisms governing this process remain incompletely understood.

Objective: We aimed to elucidate the role of Kelch-like protein 40 (KLHL40) in sarcomeric protein remodeling and calcium signaling regulation during the early stages of MI.

Methods: By integrating transcriptomic and proteomic datasets with experimental validation, we characterized dynamic changes in KLHL40 expression and its effects on sarcomeric components. KLHL40 expression was evaluated in human post-MI heart tissues and hypoxia-induced H9C2 cells. Gain- and loss-of-function assays were performed to assess its regulatory effects on key Z-disc-associated proteins (DES, MYOT, CAPZA, TCAP). Protein–protein interactions were identified via His-tag affinity capture using the OCTET NTA system, followed by mass spectrometry and enrichment analysis. Intracellular calcium levels and calpain activity were assessed, and pathways governing KLHL40 degradation were examined using specific inhibitors.

Results: KLHL40 expression was markedly upregulated within 6 hours post-MI and selectively reduced the expression of DES, MYOT, CAPZA, and TCAP—without affecting ACTN2 or FLNC—through calcium accumulation–mediated calpain activation. Interaction network analysis identified ATP2A2 and calcium signaling pathways as downstream targets. Additionally, KLHL40 turnover was regulated via the proteasomal, calpain, autophagic, and O-GlcNAcylation-dependent pathways.

Conclusion: KLHL40 serves as a key modulator of early sarcomeric remodeling following MI by promoting Z-disc protein degradation through calcium-calpain axis activation. These findings suggest KLHL40 as a potential upstream regulator and therapeutic target in post-infarction cardiac remodeling.

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