Novel and potential future biomarkers for assessment of the severity and prognosis of chronic heart failure

Virginy, David R. Buvat de

doi:10.1007/s10741-006-0234-x

Cited by 23 publications

(21 citation statements)

References 127 publications

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“…Sp1 is an oncoprotein that is critically involved in cell growth regulation and overexpresses during tumorigenesis. Recent studies also consistently demonstrated elevations of Sp1 levels in cardiac hypertrophy resulted from increased left-right shunting, volume loading of the left ventricle, pressure loading of the right ventricle, or angiotensin II stimulation [25][26][27]. In agreement with these previous studies, we also found a robust increase in Sp1 expression in left ventricular hypertrophy (Fig.…”

Section: Discussionsupporting

confidence: 92%

Transcriptional Control of Pacemaker Channel Genes HCN2 and HCN4 by Sp1 and Implications in Re-expression of These Genes in Hypertrophied Myocytes

Lin

Xiao²,

Luo³

et al. 2009

Cell Physiol Biochem

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Cardiac hypertrophy is characterized by electrical remolding with increased risk of arrhythmogenesis. Enhanced abnormal automaticity of ventricular cells may contribute to hypertrophic arrhythmias. The pacemaker current I_f, carried by the hyperpolarization-activated channels encoded mainly by the HCN2 and HCN4 genes in the heart, plays an important role in rhythmogenesis. Their expressions reportedly increase in hypertrophic and failing hearts, contributing to arrhythmogenesis under these conditions. However, how their expressions are controlled remained unclear. We performed a study to characterize the regulatory elements and transcriptional control of HCN2 and HCN4 genes. We identified the transcription start sites by 5’RACE and core promoter regions of these genes using luciferase reporter assay, and revealed the ubiquitous Sp1 protein as a common transactivator of HCN2 and HCN4 genes. We further unraveled robust increases in HCN2/HCN4 transcripts and protein levels, using real-time RT-PCR and Western blot analyses, in a rat model of left ventricular hypertrophy and in angiotensin II-induced neonatal ventricular hypertrophy. The upregulation of HCN2 and HCN4 transcription was accompanied by pronounced elevations of Sp1 and silencing of Sp1 by siRNA prevented overexpression of HCN2/HCN4 in hypertrophic cardiomyocytes. Our data indicate that Sp1 drives HCN2/HCN4 transcription and determines the functional level of HCN2/HCN4 mRNAs, and upregulation of Sp1 underlie the abnormal re-expression of HCN2/HCN4 genes in hypertrophied myocytes. This study also provides the first evidence for the role of Sp1 in the reactivation of ‘fetal’ cardiac genes, HCN2 and HCN4, in ventricular myocytes, and thereby in the pathological electrical remodeling in hypertrophied myocytes.

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Section: Discussionsupporting

confidence: 92%

Transcriptional Control of Pacemaker Channel Genes HCN2 and HCN4 by Sp1 and Implications in Re-expression of These Genes in Hypertrophied Myocytes

Lin

Xiao²,

Luo³

et al. 2009

Cell Physiol Biochem

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“…Finally, to confirm that the myocytes treated with angiotensin II indeed developed hypertrophic conditions, we measured the changes of cell size and expression of several biomarkers for cardiac hypertrophy including ␤-MHC, MLC-2, and ANF (38). As depicted in Fig.…”

Section: Role Of Mir-1 and Mir-133 In Overexpression Of F-channel Genmentioning

confidence: 94%

Down-regulation of miR-1/miR-133 Contributes to Re-expression of Pacemaker Channel Genes HCN2 and HCN4 in Hypertrophic Heart*

Luo

Lin

Pan

et al. 2008

Journal of Biological Chemistry

169

124

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Cardiac hypertrophy is characterized by electrical remolding with increased risk of arrhythmogenesis. Enhanced abnormal automaticity of ventricular cells contributes critically to hypertrophic arrhythmias. The pacemaker current I f , carried by the hyperpolarization-activated channels encoded mainly by the HCN2 and HCN4 genes in the heart, plays an important role in determining cardiac automaticity. Their expressions reportedly increase in hypertrophic and failing hearts, contributing to arrhythmogenesis under these conditions. We performed a study on post-transcriptional regulation of expression of HCN2 and HCN4 genes by microRNAs. We experimentally established HCN2 as a target for repression by the muscle-specific microRNAs miR-1 and miR-133 and established HCN4 as a target for miR-1 only. We unraveled robust increases in HCN2 and HCN4 protein levels in a rat model of left ventricular hypertrophy and in angiotensin II-induced neonatal ventricular hypertrophy. The up-regulation of HCN2/HCN4 was accompanied by pronounced reduction of miR-1/miR-133 levels. Forced expression of miR-1/miR-133 by transfection prevented overexpression of HCN2/HCN4 in hypertrophic cardiomyocytes. The serum-responsive factor protein level was found significantly decreased in hypertrophic hearts, and silencing of this protein by RNA interference resulted in increased levels of miR-1/miR-133 and concomitant increases in HCN2 and HCN4 protein levels. We conclude that down-regulation of miR-1 and miR-133 expression contributes to re-expression of HCN2/HCN4 and thereby the electrical remodeling process in hypertrophic hearts. Our study also sheds new light on the cellular function and pathological role of miR-1/miR-133 in the heart.

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“…Novel biomarkers for individualized therapy are currently under intensive investigation and may improve the clinical outcome of heart failure (HF) patients. 2,3 So far, the largest wealth of knowledge lies with measurement of b-type natriuretic peptide (BNP), which has been shown to improve clinical outcome in HF patients. 4 A hallmark of CHF is the development of myocardial remodeling and interstitial fibrosis, resulting in changes in the extracellular matrix (ECM).…”

mentioning

confidence: 99%

Plasma Biomarkers of Myocardial Fibrosis and Remodeling in Terminal Heart Failure Patients Supported by Mechanical Circulatory Support Devices

Milting¹,

Ellinghaus²,

Seewald³

et al. 2008

The Journal of Heart and Lung Transplantation

144

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Novel and potential future biomarkers for assessment of the severity and prognosis of chronic heart failure

Cited by 23 publications

References 127 publications

Transcriptional Control of Pacemaker Channel Genes <i>HCN2</i> and <i>HCN4</i> by Sp1 and Implications in Re-expression of These Genes in Hypertrophied Myocytes

Transcriptional Control of Pacemaker Channel Genes <i>HCN2</i> and <i>HCN4</i> by Sp1 and Implications in Re-expression of These Genes in Hypertrophied Myocytes

Down-regulation of miR-1/miR-133 Contributes to Re-expression of Pacemaker Channel Genes HCN2 and HCN4 in Hypertrophic Heart*

Plasma Biomarkers of Myocardial Fibrosis and Remodeling in Terminal Heart Failure Patients Supported by Mechanical Circulatory Support Devices

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