Microarray Identifies Extensive Downregulation of Noncollagen Extracellular Matrix and Profibrotic Growth Factor Genes in Chronic Isolated Mitral Regurgitation in the Dog

Zheng, Junying; Chen, Yuanwen; Pat, Betty; Dell'Italia, Louis A.; Tillson, Michael; Dillon, A. Ray; Powell, Pamela C.; Shi, Ke; Shah, Neil; Denney, Thomas S.; Husain, Ahsan

doi:10.1161/circulationaha.108.826230

Cited by 85 publications

(110 citation statements)

References 45 publications

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“…30 There is also downregulation of elastin proteins, fibrillin-1 and fibulin-1, as well as decorin, which regulates collagen fiber assembly. 31 Both tenascin-C and periostin levels are also increased, facilitating slippage between the cardiomyocytes and ECM. This is accompanied by the upregulation of inflammatory signals and downregulation of profibrotic cytokines such as TGF-β and CTGF.…”

Section: Volume Overloadmentioning

confidence: 99%

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Dynamic Changes in Myocardial Matrix and Relevance to Disease

Liu

Villarreal

et al. 2014

Circulation Research

110

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T he extracellular matrix (ECM) provides structural support and organization for cardiomyocytes and the vasculature of the heart. Under normal conditions, the ECM scaffold facilitates efficient force transduction for mechanical work, while mediating intercellular communication and metabolic exchange. This follows the unique 3-dimensional disposition of myocyte bundles and fibrillar collagens within the myocardium (Figure 1). With stress, injury, or disease, the ECM undergoes changes that potentiate inflammatory processes, myocardial protein turnover, tissue repair, and regeneration, which leads to organ remodeling and functional adaptation. However, sustained ECM remodeling can compromise proper diastolic and contractile functions as seen with fibrosis. This review will discuss the complex dynamics of the ECM in the setting of cardiovascular conditions of myocardial infarction (MI), pressure overload (PO), and volume overload (VO) as both participant and contributor to the disease pathophysiology. Subsequent sections will focus on the translational aspects of identifying biomarkers that can prognosticate or identify disease progression in patients and the current status of ECM-focused antifibrotic therapies.

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Section: Volume Overloadmentioning

confidence: 99%

“…This is accompanied by the upregulation of inflammatory signals and downregulation of profibrotic cytokines such as TGF-β and CTGF. 31 …”

Section: Volume Overloadmentioning

confidence: 99%

Dynamic Changes in Myocardial Matrix and Relevance to Disease

Liu

Villarreal

et al. 2014

Circulation Research

110

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“…Increased matrix metalloproteinase activity is associated with progressive LV dilatation and extracellular matrix degradation, contractile dysfunction, and neurohormonal activation in volume overload animal models. Zheng et al, 32 using a gene array analysis, reported recently that eccentric LV remodeling in isolated MR was associated with increased matrix metalloproteinase activity. However, we could not find a significant difference in matrix metalloproteinase families among the groups.…”

Section: Mechanism For LV Remodeling In Mrmentioning

confidence: 99%

Long-Term Effects of Sildenafil in a Rat Model of Chronic Mitral Regurgitation

Kim

Ohn²,

Yang

et al. 2012

Circulation

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Background— We tested the hypothesis that chronic treatment with sildenafil attenuates left ventricular (LV) remodeling and prevents exercise intolerance in chronic mitral regurgitation (MR). Methods and Results— MR was created in Sprague-Dawley rats by making a hole on the mitral leaflet. Two weeks after MR creation, MR and LV dilatation were confirmed by echocardiography, and rats were randomly assigned to sildenafil treatment (MR+sildenafil group; 50 mg/kg PO twice a day; n=16) or normal saline only (MR group; n=16) and continued for 4 months. Sixteen sham rats were compared with MR rats. After 4 months, LV size was smaller in the MR+sildenafil compared with the MR group (LV end-systolic dimension, 4.7±0.3 for sham versus 5.9±0.3 for MR+sildenafil versus 7.4±0.5 mm for MR; P <0.05; LV end-diastolic dimension, 8.3±0.4 versus 10.5±0.2 versus 11.7±0.61 mm, respectively; P <0.05). LV ejection fraction was greater in the MR+sildenafil group than in the MR group (70.2±2.2 for sham versus 67.0±4.2 for MR+sildenafil versus 58.9±2.5 for MR; P =0.01). Serial treadmill test revealed that exercise capacity was reduced in the MR but not in the MR+sildenafil group. Transcriptional profiling of cardiac apical tissues revealed that gene sets related to inflammatory response, DNA damage response, cell cycle checkpoint, and cellular signaling pathways were significantly enriched by genes with reciprocal changes. Pathological analysis showed that perivascular fibrosis was more prominent in the MR than in the MR+sildenafil group and that the percentage of terminal deoxynucleotidyl transferase–mediated dUTP nick-end labeling–positive cells was 2-fold greater in the MR compared with the MR+sildenafil group. Conclusions— Sildenafil significantly attenuates LV remodeling and prevents exercise intolerance in a rat model of chronic MR. This benefit may be associated with the antiapoptotic, anti-inflammatory effects of sildenafil.

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“…Most of these studies have been performed on tissue samples taken from the diseased hearts (Oyama et al 2005, Disatian et al 2008, Zheng et al 2009, Aupperle et al 2010, Obayashi et al 2011. The major drawback of these studies is the difficult in vivo acquisition of diagnostic material via i.e.…”

Section: Introductionmentioning

confidence: 99%

Correlation between peripheral blood cell transcriptomic profile and clinical parameters of chronic mitral valve disease in Dachshunds

Garncarz¹,

Hulanicka²,

Maciejewski³

et al. 2016

Polish Journal of Veterinary Sciences

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Studies identifying specific pathologically expressed genes have been performed on diseased myocardial tissue samples, however less invasive studies on gene expression of peripheral blood mononucleated cells give promising results. This study assessed transcriptomic data that may be used to evaluate Dachshunds with chronic mitral valve disease. Dachshunds with different stages of heart disease were compared to a control, healthy group. Microarray data analysis revealed clusters of patients with similar expression profiles. The clusters were compared to the clinical classification scheme. Unsupervised classification of the studied groups showed three clusters. Clinical and laboratory parameters of patients from the cluster 1 were in accordance with those found in patients without heart disease. Data obtained from patients from the cluster 3 were typical of advanced heart failure patients. Comparison of the cluster 1 and 3 groups revealed 1133 differentially expressed probes, 7 significantly regulated process pathways and 2 significantly regulated Ariadne Metabolic Pathways. This study may serve as a guideline for directing future research on gene expression in chronic mitral valve disease.

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Microarray Identifies Extensive Downregulation of Noncollagen Extracellular Matrix and Profibrotic Growth Factor Genes in Chronic Isolated Mitral Regurgitation in the Dog

Cited by 85 publications

References 45 publications

Dynamic Changes in Myocardial Matrix and Relevance to Disease

Dynamic Changes in Myocardial Matrix and Relevance to Disease

Long-Term Effects of Sildenafil in a Rat Model of Chronic Mitral Regurgitation

Correlation between peripheral blood cell transcriptomic profile and clinical parameters of chronic mitral valve disease in Dachshunds

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