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Tissue-specific miRNA Expression Profiling in Mouse Heart Sections Using In Situ Hybridization
Published on: September 15, 2018
MicroRNA-200c modulates DUSP-1 expression in diabetes-induced cardiac hypertrophy
Gurinder Bir Singh1, Satish K Raut1, Sanskriti Khanna1
1Department of Experimental Medicine and Biotechnology, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India.
Abstract:
Mitogen-activated protein kinases (MAPKs) (ERK1/2, JNK, and p38) are upregulated in diabetic cardiomyopathy (DCM). Dual-specific phosphatase-1 (DUSP-1) has been reported to regulate the activity of MAPKs in cardiac hypertrophy; however, the role of DUSP-1 in regulating MAPKs activity in DCM is not known. MicroRNAs have been reported to regulate the expression of several genes in hypertrophied failing hearts. However, little is known about the microRNAs regulating DUSP-1 expression in diabetes-related cardiac hypertrophy. In the present study, we investigated the role of DUSP-1 and miR-200c in diabetes-induced cardiac hypertrophy. DCM was induced in Wistar rats by low-dose Streptozotocin high-fat diet for 12 weeks. Cardiac expression of ERK, p-38, JNK, DUSP-1, miR-200c, and hypertrophy markers (ANP and β-MHC) was studied in DCM in control rats and in high-glucose (HG)-treated rat neonatal cardiomyocytes. miR-200c inhibition was performed to validate DUSP-1 as target. A significant increase in phosphorylated ERK, p38, and JNK was observed in DCM model and in HG-treated cardiomyocytes (p < 0.05). Expression of DUSP-1 was significantly decreased in diabetes group and in HG-treated cardiomyocytes (p < 0.05). Increased expression of miR-200c was observed in DCM model and in HG-treated cardiomyocytes (p < 0.05). Inhibition of miR-200c induces the expression of the DUSP-1 causing decreased expression of phosphorylated ERK, p38, and JNK and attenuated cardiomyocyte hypertrophy in HG-treated cardiomyocytes. miR-200c plays a role in diabetes-associated cardiac hypertrophy by modulating expression of DUSP-1.
Insights
MicroRNA-200c exacerbates diabetic cardiomyopathy by suppressing Dual-specific phosphatase-1 (DUSP-1), leading to increased mitogen-activated protein kinases (MAPKs) activity and cardiac hypertrophy.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Endocrinology
Background:
- Diabetic cardiomyopathy (DCM) involves upregulated mitogen-activated protein kinases (MAPKs).
- Dual-specific phosphatase-1 (DUSP-1) regulates MAPKs in cardiac hypertrophy, but its role in DCM is unclear.
- MicroRNAs (miRNAs) influence gene expression in cardiac hypertrophy, yet their role in regulating DUSP-1 in DCM is unknown.
Purpose of the Study:
- To investigate the role of DUSP-1 and miR-200c in diabetes-induced cardiac hypertrophy.
- To elucidate the regulatory mechanism of miR-200c on DUSP-1 expression in DCM.
Main Methods:
- Diabetic cardiomyopathy (DCM) induced in Wistar rats using streptozotocin and high-fat diet.
- Cardiac gene and protein expression analyzed (ERK, JNK, p38, DUSP-1, miR-200c, ANP, β-MHC).
- In vitro study using high-glucose treated rat neonatal cardiomyocytes with miR-200c inhibition.
Main Results:
- Increased phosphorylated ERK, p38, and JNK observed in DCM models and high-glucose treated cardiomyocytes.
- Decreased DUSP-1 expression found in DCM and high-glucose treated cardiomyocytes.
- Elevated miR-200c expression detected in DCM and high-glucose treated cardiomyocytes; miR-200c inhibition increased DUSP-1 and decreased MAPK phosphorylation, attenuating hypertrophy.
Conclusions:
- miR-200c promotes diabetes-associated cardiac hypertrophy by downregulating DUSP-1.
- Targeting miR-200c may offer a therapeutic strategy for DCM by restoring DUSP-1 levels and reducing MAPK signaling.
