The Network of Exosomes miRNA and p‐MLC2 Regulatory Pathway Induced Pathological Cardiac Hypertrophy in Vasn Deficient Mice

TL;DR

This study shows that Vasn deficiency in mice causes heart damage through exosome miRNA affecting the p-MLC2 pathway, leading to pathological cardiac hypertrophy.

Contribution

The study identifies specific miRNAs and their signaling pathways regulated by Vasn deficiency in inducing cardiac hypertrophy.

Findings

Vasn knockout mice exhibited imaging, pathological, and molecular features of pathological cardiac hypertrophy.

Exosome miRNAs let-7g-5p, let-7f-5p, and miR-148a-3p were significantly upregulated in Vasn-deficient mice.

These miRNAs target the Calm/MLCK/p-MLC2 and Rhoa/ROCK1/p-MLC2 pathways, reducing key protein expressions.

Abstract

Pathological cardiac hypertrophy was an important inducement of heart failure, cardiac arrest, and other diseases. To explore how Vasn knockout induced pathological cardiac hypertrophy, bioinformatics and functional studies illustrated the possible mechanism by clarifying the influence of exosome miRNA on the p‐MLC2 signal pathway. B‐ultrasound, electrocardiogram, pathological staining, and Q‐PCR were used to clarify the changes in typical imaging indexes, pathological indexes, and marker molecules. Exosome sequencing and bioinformatics analysis were carried out to mine key miRNA and signal pathways. Q‐PCR, IHC, and WB were used to verify the changes in miRNA and related signal pathways. The changes in heart structure and function were detected by pathological staining, electron microscopy, B‐ultrasound, and blood biochemistry in the heart tissues and blood of Vasn knockout mice. Vasn knockout mice showed typical imaging, pathological, and molecular features of PCH. Differential analysis of exosome miRNA showed that let‐7g‐5p, let‐7f‐5p, and miR‐148a‐3p significantly increased in the exosomes of Vasn‐knockout mice heart. Bioinformatics analysis showed that let‐7g‐5p and let‐7f‐5p targeted the Calm/MLCK/p‐MLC2 signal pathway, and miR‐148a‐3p targeted the Rhoa/ROCK1/p‐MLC2 signal pathway. The expression levels of miRNA were significantly up‐regulated, but related proteins of signal pathways were significantly reduced in Vasn knockout mice. The structure and function showed obvious damage in Vasn knockout mice. VASN knockout led to pathological cardiac hypertrophy, which may regulate the p‐MLC2 signalling pathway through exosomal miRNA.

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