Identification of cardiac-related circulating microRNA profile in human chronic heart failure - PubMed (original) (raw)

Huaping Li et al. Oncotarget. 2016.

Abstract

Background: During chronic heart failure, levels of circulating miRNAs endued with characteristics of diseased cells could be identified as biomarkers. In this study, we sought to identify cardiac-related circulating miRNAs as biomarkers of failing heart.

Methods: Total RNA of plasma and heart samples was extracted from 10 normal controls and 14 patients with chronic heart failure. Microarray was applied for miRNA profiles. Validation and organ/tissue distribution analysis was performed by qRT-PCR. In addition, bioinformatics analysis was performed to understand the critical roles of these cardiac-related circulating miRNAs in heart failure.

Results: Results showed that levels of more than half of the miRNAs dysregulated in heart failed to show any differences in plasma. Meanwhile, more than 90% of the miRNAs dysregulated in plasma remained stable in heart. Four cardiac fibroblast-derived miRNAs (miR-660-3p, miR-665, miR-1285-3p and miR-4491) were found significantly upregulated in heart and plasma during heart failure. These 4 miRNAs strongly discriminated patients from controls, and 3 of them showed significant correlations with LVEF.

Conclusions: This study provides global profiles of miRNAs changes in plasma and failing heart, and using a circulation-tissue miRNA profiling comparison model, we successfully identify 3 cardiac-related circulating miRNAs as potential biomarkers for diagnosis of heart failure.

Keywords: Gerotarget; circulating; heart failure; miRNA profile; tissue.

PubMed Disclaimer

Conflict of interest statement

CONFLICTS OF INTEREST

None declared.

Figures

Figure 1

Figure 1. MiRNA profiles in plasma and heart (10 control and 14 CHF patients)

A. Scatter plot of heart miRNA profiles. B. Volcano plot of heart miRNA profiles. C. Scatter plot of circulating miRNA profiles. D. Volcano plot of circulating miRNA profiles. E. 51 out of 3100 miRNAs were up-regulated and 23 miRNAs were down-regulated in heart of CHF patients. F. 347 miRNAs were up-regulated and 252 were down-regulated in plasma of CHF patients. G. Among the 51 cardiac upregulated miRNAs, 8 miRNAs were upregulated and 13 miRNAs were down-regulated in plasma. F. Among the 23 cardiac down-regulated miRNAs, 3 miRNAs were down-regulated and 8 miRNAs were upregulated in plasma.

Figure 2

Figure 2. Validation of microRNA expression by real-time PCR

Relative expression levels of each miRNA after normalization to U6 (n = 45).

Figure 3

Figure 3. Expression of cardiomyocytes-derived miRNAs

A. Cell distribution of miR-181c and miR-30c (n = 3), *p < 0.05 vs. cardiomyocytes. B. Relative expression of miR-181c-3p and miR-30c-5p in plasma of control and CHF patients (n = 45).

Figure 4

Figure 4. MiRNA expression levels correlation with disease severity

The correlation analyses between (log10)-transformed relative miRNA level (CHF patients) and individual measurements of LVEF% (n = 45).

Figure 5

Figure 5. GO and pathway analysis of the 4 cardiac fibroblast-derived miRNAs

A. GO analysis based on differentially expressed miRNA target genes. The vertical axis is the GO category and the horizontal axis is the negative logarithm of p value (−Log p), that represents the significant level of GOs. B. Pathway analysis based on differentially expressed miRNA target genes. The vertical axis is the pathway category, and the horizontal axis is the negative logarithm of p value (−Log p), that represents the significant level of pathways.

Figure 6

Figure 6. Functional network analysis of the 4 cardiac fibroblast-derived miRNAs

A. MiRNA-GOs-Network. Red box nodes represent miRNAs, and blue circular nodes represent genes. Edges show the inhibitory effect of microRNAs on GO related genes. B. Red box nodes represent miRNAs, and blue circular nodes represent pathways. Edges show the inhibitory effect of microRNAs on pathways.

References

    1. Hunt SA. American College of C and American Heart Association Task Force on Practice G. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure) J Am Coll Cardiol. 2005;46:e1–82. - PubMed
    1. Armstrong PW, Committee WS. A comparison of pharmacologic therapy with/without timely coronary intervention vs. primary percutaneous intervention early after ST-elevation myocardial infarction: the WEST (Which Early ST-elevation myocardial infarction Therapy) study. Eur Heart J. 2006;27:1530–1538. - PubMed
    1. Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, de Ferranti S, Despres JP, Fullerton HJ, Howard VJ, Huffman MD, Judd SE, Kissela BM, et al. Heart disease and stroke statistics—2015 update: a report from the American Heart Association. Circulation. 2015;131:e29–322. - PubMed
    1. de Boer RA, Daniels LB, Maisel AS, Januzzi JL., Jr State of the Art: Newer biomarkers in heart failure. Eur J Heart Fail. 2015;17:559–69. doi: 10.1002/ejhf.273. - DOI - PubMed
    1. van Rooij E. The art of microRNA research. Circ Res. 2011;108:219–234. - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources