Dataset Information

Mechanosensitive microRNA-181b Regulates Aortic Valve Endothelial Matrix Degradation by Targeting TIMP3.

ABSTRACT: Calcific aortic valve disease (CAVD) is a major cause of morbidity in the aging population, but the underlying mechanisms of its progression remain poorly understood. Aortic valve calcification preferentially occurs on the fibrosa, which is subjected to disturbed flow. The side-specific progression of the disease is characterized by inflammation, calcific lesions, and extracellular matrix (ECM) degradation. Here, we explored the role of mechanosensitive microRNA-181b and its downstream targets in human aortic valve endothelial cells (HAVECs). Mechanistically, miR-181b is upregulated in OS and fibrosa, and it targets TIMP3, SIRT1, and GATA6, correlated with increased gelatinase/MMP activity. Overexpression of miR-181b led to decreased TIMP3 and exacerbated MMP activity as shown by gelatinase assay, and miR-181b inhibition decreased gelatinase activity through the repression of TIMP3 levels. Luciferase assay showed specific binding of miR-181b to the TIMP3 gene. Overexpression of miR-181b in HAVECs subjected to either LS or OS increased MMP activity, and miR-181b inhibition abrogated shear-sensitive MMP activity. These studies suggest that targeting this shear-dependent miRNA may provide a novel noninvasive treatment for CAVD.

SUBMITTER: Heath JM

PROVIDER: S-EPMC5568995 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Mechanosensitive microRNA-181b Regulates Aortic Valve Endothelial Matrix Degradation by Targeting TIMP3.

Heath Jack M JM Fernandez Esmerats Joan J Khambouneheuang Lucky L Kumar Sandeep S Simmons Rachel R Jo Hanjoong H

Cardiovascular engineering and technology 20170224 2

Calcific aortic valve disease (CAVD) is a major cause of morbidity in the aging population, but the underlying mechanisms of its progression remain poorly understood. Aortic valve calcification preferentially occurs on the fibrosa, which is subjected to disturbed flow. The side-specific progression of the disease is characterized by inflammation, calcific lesions, and extracellular matrix (ECM) degradation. Here, we explored the role of mechanosensitive microRNA-181b and its downstream targets i ...[more]

PMID: 28236165

Similar Datasets

Project description:Multiple molecular and cellular mechanisms are associated with the initiation and progression of aortic valve disease. Alterations in ECM remodeling, increased expression of pro-inflammatory cytokines, calcification, lipid deposition and changes in valve cell phenotype have demonstrated roles in development of aortic valve disease. Mechanical stimulation has a significant role in determining the physiological properties of valve tissue and an altered hemodynamic environment may result in pathological changes. We used microarrays to detail the global of gene expression profiles underlying valve remodeling during valve exposure to of two levels of cyclic mechanical pressure (normotensive 0-80mmHg and hypertensive 0-120mmHg ) on porcine valve tissue transcriptome using Sus Scrofa cDNA microarrays from Affymetrix and we identified distinct classes of up-regulated genes during this process. Hybridizations were carried out with RNA isolated from six independetn samples of valve tissue exposed to normotensive and hypertensive pressure for 24 hours at 1hz frecuency. Differentially expressed genes were identified by The t test with the option of unequal variance was used to calculate P values for each gene. The fold change and Q values for each gene were calculated with SAM program with permutation of 500 . Biological modeling of the differentially expressed genes (DE) was carried out based on GO groups and network analysis in ingenuity Pathway Analysis (IPA). Experiment Overall Design: The experimental design included three biological samples of porcine valve leaflets exposed to cyclic pressures of 0-80 or 0-120 mmHg for 24 hours, representing normotensive and hypertensive diastolic transvalvular pressure, respectively. Using Affymetrix porcine microarrays, we compared global gene expression profiles of aortic valve leaflets exposed to elevated and normal physiological pressure conditions . The effects of cyclic pressure on the transcriptome was determined by comparing the quantity and magnitud of change in gene expression levels of valve leflets, as well evaluating the molecular function each gene has in the cell,in the presence of hypertennsive (experimental) and normotensve pressurec (control).

Dataset Information

Mechanosensitive microRNA-181b Regulates Aortic Valve Endothelial Matrix Degradation by Targeting TIMP3.

Publications

Mechanosensitive microRNA-181b Regulates Aortic Valve Endothelial Matrix Degradation by Targeting TIMP3.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure