Construction of a Human Cardiovascular cDNA Microarray: Portrait of the Failing Heart

doi:10.1006/bbrc.2000.4137

Biochemical and Biophysical Research Communications

Volume 280, Issue 4, 2 February 2001, Pages 964-969

https://doi.org/10.1006/bbrc.2000.4137 Get rights and content

Abstract

Identifying key genes that regulate the complex diseases of the cardiovascular system can be greatly facilitated with the use of microarrays. In an effort to obtain a global portrait of gene expression in the failing heart, we have constructed in-house a glass microscope slide cDNA microarray (termed “CardioChip”) containing 10,368 redundant and randomly-selected sequenced expressed sequence tags (representing known genes, other matched ESTs, and novel, unmatched ESTs) derived from several human heart and artery cDNA libraries. From our preliminary data with Cy3- and Cy5-labeled probes, we have identified 38 transcripts showing a minimum twofold differential expression, among which are several novel or previously-uncharacterized genes. This array—representing what we believe to be the largest cardiovascular-based cDNA array to date—establishes a practical and invaluable platform for obtaining a global genetic portrait of complex cardiovascular diseases, particularly in the failing heart.

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In addition, to evaluate the specificity of these 608 immunological signatures for immune systems, we inspected the involvement of the immunological signatures in seven gene expression profiles of different cardiomyopathy subtypes from a same experiment (GEO accession: GSE2656; Supplementary table 2). This experiment utilizes a homemade cDNA microarray (termed CardioChip; GEO accession: GPL2041), containing 10,368 sequence tags specifically derived from human heart and artery cDNA libraries and applied to detecting the portrait of the failing heart, thus, does not provides adequate coverage on the immune systems related genes [14]. For the 7 heart diseases, we would expect that the 608 immunological signatures have no significant associations with their transcriptional profiles (FDR > 0.05).
Dysregulated immune system has been implicated in the pathogenesis of various cardiovascular diseases. Therefore, development of pharmacological interventions targeting the immune system is promising. However, therapy with most common anti-inflammatory and immunomodulatory agents has proved challenging in the clinical translation. It has been proved that many herbal ingredients display definite therapeutic effects on preventing excessive inflammatory and immune responses. Here, we aim to systemically explore the immunomodulatory ability of herbal ingredients on the human heart tissue-specific immune dysfunction through a network pharmacology based approach. The approach matches gene expression data between herbal ingredients and human heart phenotype based on their immunological similarities. Firstly, 608 immunological signatures were produced from 304 transcriptional profiles of immunological cell state changes. Then, the immunological features of 28 human heart phenotypes and 102 herbal ingredients were constructed by calculating the enrichments of each immune signature in the transcriptional profiles of heart phenotypes and herbal ingredients, respectively. Finally, the likelihood that an herbal drug affects the immune system in a heart phenotype was qualified by calculating the immunological similarity between the herbal drug and the heart phenotype. This strategy integrating different types of OMICs data is expected to help create new opportunities for development of drugs targeting the immune dysfunction in heart disease.
Association of expression of ZNF606 gene from monocytes with the risk of coronary artery disease
2018, Clinical Biochemistry
Citation Excerpt :
As a result, monocytes may act as a potential target for diagnosing the risk associated with CAD and as a promising therapy. Next-generation sequencing and high-density microarrays have been established as novel methods for CAD study [32], which provides us with more information regarding the changes of gene expression during the disease development. ZNF606 is a zinc finger protein that contains a Kruppel-associated box domain (KRAB) in the N-terminal end, and functions as a transcriptional repression domain.
Messenger RNAs (mRNAs) play an important role in the pathogenesis of coronary artery disease (CAD). We evaluated the association of selected increase in mRNAs from monocytes with the risk of CAD.
Chip data (GSE9820) retrieved from Gene Expression Omnibus (GEO) was re-analyzed, and the selected candidate genes, meeting specific conditions, were up-regulated and verified for specific biomarkers of CAD within a prospective cohort study that recruited 194 individuals and subdivided into two groups: group Non-CAD (GN), n = 68 and group CAD (GC), n = 126. The patients in GC were further categorized into three sub-units according to the extent of coronary stenosis shown during coronary angiography, coded as single-vessel stenosis (GC1, n = 53), 2-vessel stenosis (GC2, n = 50), or ≥ 3-vessel stenosis (GC3, n = 23). All candidate mRNAs expressions were analyzed from patients' monocytes with quantitative PCR (q-PCR). Receiver-operating characteristic (ROC) curves and the area under the ROC curves (AUCs) were used to evaluate the mRNAs' feasibility for CAD prediction. AUCs ≥0.8 were accounted as highly specific association with CAD.
GBA2, CSTF3, ZNF606 and MPP5 were selected as mRNAs candidates from chip data reanalysis. GBA2 (P = .002) and ZNF606 (P < .001) expressions were significantly increased in GC. ZNF606 showed significant increase after adjusting the risk factors with logistic regression analysis (OR = 3.804, 95% CI: 1.923, 7.798, P < .001), and its expression level was positively correlated with age (β = 0.04 × 10⁻³, P < .001). The AUCs (and 95% CI) of ZNF606 expression in GC2 and GC3 were ≥0.8.
These findings suggest that it is novel and specific for the association of ZNF606 gene expression from monocytes with the risk of CAD, especially in patients with multiple coronary artery stenosis.
Overexpression of prostaglandin E2 EP4 receptor improves cardiac function after myocardial infarction
2018, Journal of Molecular and Cellular Cardiology
Prostaglandin E2 (PGE₂) signals through 4 separate G-protein coupled receptor sub-types to elicit a variety of physiologic and pathophysiological effects. We recently reported that PGE₂ via its EP3 receptor could reduce cardiac contractility of isolated myocytes and the working heart preparation. We thus hypothesized that there is an imbalance in the EP3/EP4 ratio towards EP3 in the failing heart and that overexpression of EP4 in a mouse model of heart failure would improve cardiac function.
Our hypothesis was tested in a mouse model of myocardial infarction (MI) with the use of AAV9-EP4 driven by the myosin heavy chain promoter to overexpress EP4 in the cardiac myocytes. Echocardiography was performed to assess cardiac function. We found that overexpression of EP4 improved shortening fraction (p = 0.0025), ejection fraction (p = 0.0003), and reduced left ventricular dimension at systole (p = 0.0013). Overexpression of EP4 also significantly reduced indices of cardiac hypertrophy and interstitial collagen fraction. Animals treated with AAV9-EP4 also had a significant decrease in TNFα mRNA expression and in the number of macrophages and T cells migrated post MI coupled with a reduction in the expression of iNOS.
Overexpression of EP4 improves cardiac function post MI. This may be mediated through reductions in adverse cardiac remodeling or via inhibition of cytokine/chemokine production.
Molecular distinction between physiological and pathological cardiac hypertrophy: Experimental findings and therapeutic strategies
2010, Pharmacology and Therapeutics
Citation Excerpt :
The enhanced oxidative capacity of hearts that have undergone physiological hypertrophy suggests a protected phenotype. In another approach to identify transcriptome changes associated with pathological and physiological cardiac hypertrophy, a number of investigators have conducted comprehensive microarray gene expression profiling studies in hearts from rodent models of pathological and physiological cardiac hypertrophy, as well as tissue from heart failure patients (Friddle et al., 2000; Hwang et al., 2000; Yang et al., 2000; Barrans et al., 2001; Hwang et al., 2002b; Diffee et al., 2003; McMullen et al., 2004b; Kong et al., 2005; Strom et al., 2005). More recent studies have used proteomic methods, such as 2-dimensional polyacrylamide gel electrophoresis (2-D PAGE) in conjunction with mass spectrometry to catalogue exercise-induced changes in the cardiac proteome (Boluyt et al., 2006; Burniston, 2009).
Cardiac hypertrophy can be defined as an increase in heart mass. Pathological cardiac hypertrophy (heart growth that occurs in settings of disease, e.g. hypertension) is a key risk factor for heart failure. Pathological hypertrophy is associated with increased interstitial fibrosis, cell death and cardiac dysfunction. In contrast, physiological cardiac hypertrophy (heart growth that occurs in response to chronic exercise training, i.e. the ‘athlete's heart’) is reversible and is characterized by normal cardiac morphology (i.e. no fibrosis or apoptosis) and normal or enhanced cardiac function. Given that there are clear functional, structural, metabolic and molecular differences between pathological and physiological hypertrophy, a key question in cardiovascular medicine is whether mechanisms responsible for enhancing function of the athlete's heart can be exploited to benefit patients with pathological hypertrophy and heart failure. This review summarizes key experimental findings that have contributed to our understanding of pathological and physiological heart growth. In particular, we focus on signaling pathways that play a causal role in the development of pathological and physiological hypertrophy. We discuss molecular mechanisms associated with features of cardiac hypertrophy, including protein synthesis, sarcomeric organization, fibrosis, cell death and energy metabolism and provide a summary of profiling studies that have examined genes, microRNAs and proteins that are differentially expressed in models of pathological and physiological hypertrophy. How gender and sex hormones affect cardiac hypertrophy is also discussed. Finally, we explore how knowledge of molecular mechanisms underlying pathological and physiological hypertrophy may influence therapeutic strategies for the treatment of cardiovascular disease and heart failure.
Transcriptomics: Translation of Global Expression Analysis to Genomic Medicine
2009, Genomic and Personalized Medicine, Two-Vol Set
Transcriptomics: Translation of Global Expression Analysis to Genomic Medicine
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Regular ArticleConstruction of a Human Cardiovascular cDNA Microarray: Portrait of the Failing Heart

Abstract

Genomics

Mol. Med. Today

J. Mol. Cell. Cardiol.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Cell

Cell

Biochem. Biophys. Res. Commun.

A genome-based resource for molecular cardiovascular medicine: Toward a compendium of cardiovascular genes

Circulation

A catalogue of genes in the cardiovascular system as identified by expressed sequence tags

Proc. Natl. Acad. Sci. USA

Construction of a human heart cDNA library and identification of cardiovascular based genes (CVBest)

Mol. Cell Biochem.

Use of a cDNA microarray to analyse gene expression patterns in human cancer

Nat. Genet.

Expression profiling using DNA microarrays

Nat. Genet.

Genome-wide expression profiling of mid-gestation placenta and embryo using a 15,000 mouse developmental cDNA microarray

Proc. Natl. Acad. Sci. USA

Regular Article
Construction of a Human Cardiovascular cDNA Microarray: Portrait of the Failing Heart