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In Vivo Nanovector Delivery of a Heart-specific MicroRNA-sponge
Published on: June 15, 2018
MicroRNAs are involved in homocysteine-induced cardiac remodeling
Paras K Mishra1, Neetu Tyagi, Soumi Kundu
1Department of Physiology & Biophysics, University of Louisville, School of Medicine, A-1215, 500 South Preston Street, Louisville, KY, 40202, USA.
Insights
Elevated homocysteine (Hcy) causes heart failure by altering cardiac remodeling. This study reveals dicer and microRNA-188 (miR-188) play key roles in this process, offering new insights into heart disease mechanisms.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Biochemistry
Background:
- Hyperhomocysteinemia (HHcy), an elevated homocysteine (Hcy) level, is a significant risk factor for chronic heart failure.
- The precise molecular mechanisms underlying Hcy's role in cardiac remodeling remain unclear.
- MicroRNAs (miRNAs) and the enzyme Dicer are recognized regulators in cardiovascular diseases.
Purpose of the Study:
- To investigate the involvement of Dicer and specific miRNAs in Hcy-induced cardiac remodeling.
- To elucidate the regulatory pathways affected by Hcy in cardiomyocytes.
- To identify key molecular players in HHcy-related cardiac pathology.
Main Methods:
- HL-1 cardiomyocytes were exposed to varying concentrations of Hcy.
- Gene and protein expression analysis using RT-PCR, real-time PCR, and Western blotting for Dicer, MMPs, TIMPs, and NOX-4.
- MiRNA expression profiling via microarray analysis and individual miRNA assays.
Main Results:
- Dicer expression was upregulated in HHcy cardiomyocytes, suggesting its involvement in remodeling.
- High Hcy doses increased NOX-4 expression, indicating elevated oxidative stress.
- Cardiac remodeling markers (MMP-2, MMP-9, TIMP-1, TIMP-3) were elevated, while TIMP-4 was reduced.
- MiRNA microarray identified differential expression of 11 miRNAs, with a notable downregulation of miR-188.
Conclusions:
- Dicer and specific miRNAs, particularly miR-188, are implicated in the pathogenesis of Hcy-induced cardiac remodeling.
- Oxidative stress, mediated by factors like NOX-4, contributes to cardiac remodeling in HHcy.
- These findings highlight a novel regulatory axis involving Dicer and miRNAs in heart failure progression.
Abstract:
Elevated level of homocysteine (Hcy) called hyperhomocysteinemia (HHcy) is one of the major risk factors for chronic heart failure. Although the role of Hcy in cardiac remodeling is documented, the regulatory mechanism involved therein is still nebulous. MicroRNAs (miRNAs) and dicer have been implicated in regulation of cardiovascular diseases. Dicer is the only known enzyme involved in miRNA maturation. We investigated the involvement of dicer and miRNA in Hcy-induced cardiac remodeling. HL-1 cardiomyocytes were cultured in different doses of Hcy. Total RNA was isolated and RT-PCR and real-time PCR was performed for dicer, MMP-2,-9, TIMP-1,-3, and NOX-4. MiRNA microarray was used for analyzing the differential expression of miRNAs. Individual miRNA assay was also done. Western blotting was used to assess the MMP-9 expression in HHcy cardiomyocytes. The RT-PCR results suggest that dicer expression is enhanced in HHcy cardiomyocytes suggesting its involvement in cardiac remodeling caused due to high dose of Hcy. On the other hand, high dose of Hcy increased NOX-4 expression, a marker for oxidative stress. Additionally, HHcy cardiomyocytes showed elevated levels of MMP-2,-9 and TIMP-1,-3, and reduced expression of TIMP-4, suggesting cardiac remodeling due to oxidative stress. The miRNA microarray assay revealed differential expression of 11 miRNAs and among them miR-188 show dramatic downregulation. These findings suggest that dicer and miRNAs especially miR-188 are involved in Hcy-induced cardiac remodeling.
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