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Identification of side- and shear-dependent microRNAs regulating porcine aortic valve pathogenesis.

ABSTRACT: Aortic valve (AV) calcification is an inflammation driven process that occurs preferentially in the fibrosa. To explore the underlying mechanisms, we investigated if key microRNAs (miRNA) in the AV are differentially expressed due to disturbed blood flow (oscillatory shear (OS)) experienced by the fibrosa compared to the ventricularis. To identify the miRNAs involved, endothelial-enriched RNA was isolated from either side of healthy porcine AVs for microarray analysis. Validation using qPCR confirmed significantly higher expression of 7 miRNAs (miR-100, -130a, -181a/b, -199a-3p, -199a-5p, and -214) in the fibrosa versus the ventricularis. Upon bioinformatics analysis, miR-214 was selected for further investigation using porcine AV leaflets in an ex vivo shear system. Fibrosa and ventricularis sides were exposed to either oscillatory or unidirectional pulsatile shear for 2 days and 3 &7 days in regular and osteogenic media, respectively. Higher expression of miR-214, increased thickness of the fibrosa, and calcification was observed when the fibrosa was exposed to OS compared to the ventricularis. Silencing of miR-214 by anti-miR-214 in whole AV leaflets with the fibrosa exposed to OS significantly increased the protein expression of TGF?1 and moderately increased collagen content but did not affect AV calcification. Thus, miR-214 is identified as a side- and shear-dependent miRNA that regulates key mechanosensitive gene in AV such as TGF?1.

SUBMITTER: Rathan S

PROVIDER: S-EPMC4858741 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Identification of side- and shear-dependent microRNAs regulating porcine aortic valve pathogenesis.

Rathan Swetha S Ankeny Casey J CJ Arjunon Sivakkumar S Ferdous Zannatul Z Kumar Sandeep S Fernandez Esmerats Joan J Heath Jack M JM Nerem Robert M RM Yoganathan Ajit P AP Jo Hanjoong H

Scientific reports 20160506

Aortic valve (AV) calcification is an inflammation driven process that occurs preferentially in the fibrosa. To explore the underlying mechanisms, we investigated if key microRNAs (miRNA) in the AV are differentially expressed due to disturbed blood flow (oscillatory shear (OS)) experienced by the fibrosa compared to the ventricularis. To identify the miRNAs involved, endothelial-enriched RNA was isolated from either side of healthy porcine AVs for microarray analysis. Validation using qPCR conf ...[more]

PMID: 27151744

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Project description:OBJECTIVES:Bicuspid aortic valve, characterized by valve malformation and risk for aortopathy, displays profound alteration in systolic aortic outflow and wall shear stress distribution. The present study performed 4-dimensional flow magnetic resonance imaging in patients with bicuspid aortic valve with right-left cusp fusion, focusing on the impact of valve function on hemodynamic status within the ascending aorta. METHODS:Four-dimensional flow magnetic resonance imaging was performed in 50 subjects with right-left bicuspid aortic valve and 15 age- and aortic size-matched controls with tricuspid aortic valve. Patients with bicuspid aortic valve were categorized into 3 groups according to their aortic valve function as follows: bicuspid aortic valve with no more than mild aortic valve dysfunction (bicuspid aortic valve control, n = 20), bicuspid aortic valve with severe aortic insufficiency (n = 15), and bicuspid aortic valve with severe aortic stenosis (n = 15). RESULTS:All patients with right-left bicuspid aortic valve exhibited peak wall shear stress at the right-anterior position of the ascending aorta (bicuspid aortic valve vs trileaflet aortic valve at the right-anterior position: 0.91 ± 0.23 N/m2 vs 0.43 ± 0.12 N/m2, P < .001) with no distinct alteration between bicuspid aortic valve with severe aortic insufficiency and bicuspid aortic valve with severe aortic stenosis. The predominance of dilatation involving the tubular ascending aorta (82%, type 2 aortopathy) persisted, with or without valve dysfunction. Compared with bicuspid aortic valve control subjects, the bicuspid aortic valve with severe aortic insufficiency group displayed universally elevated wall shear stress (0.75 ± 0.12 N/m2 vs 0.57 ± 0.09 N/m2, P < .01) in the ascending aorta, which was associated with elevated cardiac stroke volume (P < .05). The bicuspid aortic valve with severe aortic stenosis group showed elevated flow eccentricity in the form of significantly increased standard deviation of circumferential wall shear stress, which correlated with markedly increased peak aortic valve velocity (P < .01). CONCLUSIONS:The location of peak aortic wall shear stress and type of aortopathy remained homogeneous among patients with right-left bicuspid aortic valve irrespective of valve dysfunction. Severe aortic insufficiency or stenosis resulted in further elevated aortic wall shear stress and exaggerated flow eccentricity.

Project description:OBJECTIVES:The objectives of this study were to investigate an association between the magnitude of flow-mediated aortic wall shear stress (WSS) and medial wall histopathology in patients with bicuspid aortic valve (BAV) with aortopathy. METHODS:Patients with BAV (n = 27; 52 ± 15 years; 3 women; proximal thoracic aorta diameter = 4.4 ± 0.7 and 4.6 ± 0.5 cm) who underwent prophylactic aortic resection received preoperative 3-dimensional time-resolved phase-contrast magnetic resonance imaging with 3-dimensional velocity encoding to quantify WSS relative to a population of healthy age- and sex-matched tricuspid aortic valve control participants (n = 20). Quantitative histopathology was conducted on BAV aorta tissue samples resected at surgery (n = 93), and correlation was performed between elastic fiber thickness and in vivo aortic WSS as continuous variables. Validation of elastic fiber thickness was achieved by correlation relative to tissue stiffness determined using biaxial biomechanical testing (n = 22 samples). RESULTS:Elastic fibers were thinner and WSS was higher along the greater curvature compared with other circumferential regions (vs anterior wall: P = .003 and P = .0001, respectively; lesser curvature: both P = .001). Increased regional WSS was associated with decreased elastic fiber thickness (r = -0.25; P = .02). Patient stratification with subanalysis showed an increase in the correlation between WSS and histopathology with aortic valve stenosis (r = -0.36; P = .002) and smaller aortic diameters (<4.5 cm: r = -0.39; P = .03). Elastic fiber thinning was associated with circumferential stiffness (r = -0.41; P = .06). CONCLUSIONS:For patients with BAV, increased aortic valve-mediated WSS is significantly associated with elastic fiber thinning, particularly with aortic valve stenosis and in earlier stages of aortopathy. Elastic fiber thinning correlates with impaired tissue biomechanics. These novel findings further implicate valve-mediated hemodynamics in the progression of BAV aortopathy.

Dataset Information

Identification of side- and shear-dependent microRNAs regulating porcine aortic valve pathogenesis.

Publications

Identification of side- and shear-dependent microRNAs regulating porcine aortic valve pathogenesis.

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