Gene Expression Profiles of Peripheral Blood Mononuclear Cells Reveal Transcriptional Signatures as Novel Biomarkers of Cardiac Remodeling in Rats With Aldosteronism and Hypertensive Heart Disease

Ivan Gerling, Robert A. Ahokas, German Kamalov, Wenyuan Zhao, Syamal Bhattacharya, Yao Sun, Karl Weber

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11 Citations (Scopus)

Abstract

Objectives: In searching for a noninvasive surrogate tissue mimicking the pro-oxidant/proinflammatory hypertensive heart disease (HHD) phenotype, we turned to peripheral blood mononuclear cells (PBMCs). We tested whether iterations in [Ca2+]i, [Zn2+]i, and oxidative stress in cardiomyocytes and PBMCs would complement each other, eliciting similar shifts in gene expression profiles in these tissues demonstrable during the preclinical (week 1) and pathological (week 4) stages of aldosterone/salt treatment (ALDOST). Background: Inappropriate neurohormonal activation contributes to pathological remodeling of myocardium in HHD associated with aldosteronism. In rats receiving long-term ALDOST, evidence of reparative fibrosis replacing necrotic cardiomyocytes and coronary vasculopathy appears at week 4 associated with the induction of oxidative stress by mitochondria that overwhelms endogenous, largely Zn2+-based, antioxidant defenses. Biomarker-guided prediction of risk before the appearance of cardiac pathology would prove invaluable. Methods: In PBMCs and cardiomyocytes, quantitation of cytoplasmic free Ca2+ and Zn2+, H2O2, and 8-iosprostane levels and isolation of ribonucleic acid (RNA) and gene expression together with statistical and clustering analyses and confirmation of genes by in situ hybridization and reverse-transcription polymerase chain reaction were performed. Results: Compared with controls, at weeks 1 and 4 of ALDOST, we found comparable increments in [Ca2+]i, [Zn2+]i, and 8-isoprotane coupled with increased H2O2 production in cardiac mitochondria and PBMCs, together with the common networks of expression profiles dominated by genes involved in oxidative stress, inflammation, and repair. These included 3 central Ingenuity pathway-linked genes: p38 mitogen-activated protein kinase, a stress-responsive protein; nuclear factor-κB, a redox-sensitive transcription factor and a proinflammatory cascade that it regulates; and transforming growth factor-β1, a fibrogenic cytokine involved in tissue repair. Conclusions: Significant overlapping demonstrated in the molecular mimicry of PBMCs and cardiomyocytes during preclinical and pathological stages of ALDOST implies that transcriptional signatures of PBMCs may serve as early noninvasive and novel sentinels predictive of impending pathological remodeling in HHD.

Original languageEnglish (US)
Pages (from-to)469-476
Number of pages8
JournalJACC: Heart Failure
Volume1
Issue number6
DOIs
StatePublished - Jan 1 2013

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Hyperaldosteronism
Transcriptome
Heart Diseases
Blood Cells
Biomarkers
Aldosterone
Cardiac Myocytes
Salts
Oxidative Stress
Mitochondria
Molecular Mimicry
Transforming Growth Factors
p38 Mitogen-Activated Protein Kinases
Heat-Shock Proteins
Genes
Reverse Transcription
Oxidation-Reduction
In Situ Hybridization
Cluster Analysis
Reactive Oxygen Species

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

Cite this

@article{47b1434304e24724979bb0c03b848879,
title = "Gene Expression Profiles of Peripheral Blood Mononuclear Cells Reveal Transcriptional Signatures as Novel Biomarkers of Cardiac Remodeling in Rats With Aldosteronism and Hypertensive Heart Disease",
abstract = "Objectives: In searching for a noninvasive surrogate tissue mimicking the pro-oxidant/proinflammatory hypertensive heart disease (HHD) phenotype, we turned to peripheral blood mononuclear cells (PBMCs). We tested whether iterations in [Ca2+]i, [Zn2+]i, and oxidative stress in cardiomyocytes and PBMCs would complement each other, eliciting similar shifts in gene expression profiles in these tissues demonstrable during the preclinical (week 1) and pathological (week 4) stages of aldosterone/salt treatment (ALDOST). Background: Inappropriate neurohormonal activation contributes to pathological remodeling of myocardium in HHD associated with aldosteronism. In rats receiving long-term ALDOST, evidence of reparative fibrosis replacing necrotic cardiomyocytes and coronary vasculopathy appears at week 4 associated with the induction of oxidative stress by mitochondria that overwhelms endogenous, largely Zn2+-based, antioxidant defenses. Biomarker-guided prediction of risk before the appearance of cardiac pathology would prove invaluable. Methods: In PBMCs and cardiomyocytes, quantitation of cytoplasmic free Ca2+ and Zn2+, H2O2, and 8-iosprostane levels and isolation of ribonucleic acid (RNA) and gene expression together with statistical and clustering analyses and confirmation of genes by in situ hybridization and reverse-transcription polymerase chain reaction were performed. Results: Compared with controls, at weeks 1 and 4 of ALDOST, we found comparable increments in [Ca2+]i, [Zn2+]i, and 8-isoprotane coupled with increased H2O2 production in cardiac mitochondria and PBMCs, together with the common networks of expression profiles dominated by genes involved in oxidative stress, inflammation, and repair. These included 3 central Ingenuity pathway-linked genes: p38 mitogen-activated protein kinase, a stress-responsive protein; nuclear factor-κB, a redox-sensitive transcription factor and a proinflammatory cascade that it regulates; and transforming growth factor-β1, a fibrogenic cytokine involved in tissue repair. Conclusions: Significant overlapping demonstrated in the molecular mimicry of PBMCs and cardiomyocytes during preclinical and pathological stages of ALDOST implies that transcriptional signatures of PBMCs may serve as early noninvasive and novel sentinels predictive of impending pathological remodeling in HHD.",
author = "Ivan Gerling and Ahokas, {Robert A.} and German Kamalov and Wenyuan Zhao and Syamal Bhattacharya and Yao Sun and Karl Weber",
year = "2013",
month = "1",
day = "1",
doi = "10.1016/j.jchf.2013.09.003",
language = "English (US)",
volume = "1",
pages = "469--476",
journal = "JACC: Heart Failure",
issn = "2213-1779",
publisher = "Elsevier BV",
number = "6",

}

TY - JOUR

T1 - Gene Expression Profiles of Peripheral Blood Mononuclear Cells Reveal Transcriptional Signatures as Novel Biomarkers of Cardiac Remodeling in Rats With Aldosteronism and Hypertensive Heart Disease

AU - Gerling, Ivan

AU - Ahokas, Robert A.

AU - Kamalov, German

AU - Zhao, Wenyuan

AU - Bhattacharya, Syamal

AU - Sun, Yao

AU - Weber, Karl

PY - 2013/1/1

Y1 - 2013/1/1

N2 - Objectives: In searching for a noninvasive surrogate tissue mimicking the pro-oxidant/proinflammatory hypertensive heart disease (HHD) phenotype, we turned to peripheral blood mononuclear cells (PBMCs). We tested whether iterations in [Ca2+]i, [Zn2+]i, and oxidative stress in cardiomyocytes and PBMCs would complement each other, eliciting similar shifts in gene expression profiles in these tissues demonstrable during the preclinical (week 1) and pathological (week 4) stages of aldosterone/salt treatment (ALDOST). Background: Inappropriate neurohormonal activation contributes to pathological remodeling of myocardium in HHD associated with aldosteronism. In rats receiving long-term ALDOST, evidence of reparative fibrosis replacing necrotic cardiomyocytes and coronary vasculopathy appears at week 4 associated with the induction of oxidative stress by mitochondria that overwhelms endogenous, largely Zn2+-based, antioxidant defenses. Biomarker-guided prediction of risk before the appearance of cardiac pathology would prove invaluable. Methods: In PBMCs and cardiomyocytes, quantitation of cytoplasmic free Ca2+ and Zn2+, H2O2, and 8-iosprostane levels and isolation of ribonucleic acid (RNA) and gene expression together with statistical and clustering analyses and confirmation of genes by in situ hybridization and reverse-transcription polymerase chain reaction were performed. Results: Compared with controls, at weeks 1 and 4 of ALDOST, we found comparable increments in [Ca2+]i, [Zn2+]i, and 8-isoprotane coupled with increased H2O2 production in cardiac mitochondria and PBMCs, together with the common networks of expression profiles dominated by genes involved in oxidative stress, inflammation, and repair. These included 3 central Ingenuity pathway-linked genes: p38 mitogen-activated protein kinase, a stress-responsive protein; nuclear factor-κB, a redox-sensitive transcription factor and a proinflammatory cascade that it regulates; and transforming growth factor-β1, a fibrogenic cytokine involved in tissue repair. Conclusions: Significant overlapping demonstrated in the molecular mimicry of PBMCs and cardiomyocytes during preclinical and pathological stages of ALDOST implies that transcriptional signatures of PBMCs may serve as early noninvasive and novel sentinels predictive of impending pathological remodeling in HHD.

AB - Objectives: In searching for a noninvasive surrogate tissue mimicking the pro-oxidant/proinflammatory hypertensive heart disease (HHD) phenotype, we turned to peripheral blood mononuclear cells (PBMCs). We tested whether iterations in [Ca2+]i, [Zn2+]i, and oxidative stress in cardiomyocytes and PBMCs would complement each other, eliciting similar shifts in gene expression profiles in these tissues demonstrable during the preclinical (week 1) and pathological (week 4) stages of aldosterone/salt treatment (ALDOST). Background: Inappropriate neurohormonal activation contributes to pathological remodeling of myocardium in HHD associated with aldosteronism. In rats receiving long-term ALDOST, evidence of reparative fibrosis replacing necrotic cardiomyocytes and coronary vasculopathy appears at week 4 associated with the induction of oxidative stress by mitochondria that overwhelms endogenous, largely Zn2+-based, antioxidant defenses. Biomarker-guided prediction of risk before the appearance of cardiac pathology would prove invaluable. Methods: In PBMCs and cardiomyocytes, quantitation of cytoplasmic free Ca2+ and Zn2+, H2O2, and 8-iosprostane levels and isolation of ribonucleic acid (RNA) and gene expression together with statistical and clustering analyses and confirmation of genes by in situ hybridization and reverse-transcription polymerase chain reaction were performed. Results: Compared with controls, at weeks 1 and 4 of ALDOST, we found comparable increments in [Ca2+]i, [Zn2+]i, and 8-isoprotane coupled with increased H2O2 production in cardiac mitochondria and PBMCs, together with the common networks of expression profiles dominated by genes involved in oxidative stress, inflammation, and repair. These included 3 central Ingenuity pathway-linked genes: p38 mitogen-activated protein kinase, a stress-responsive protein; nuclear factor-κB, a redox-sensitive transcription factor and a proinflammatory cascade that it regulates; and transforming growth factor-β1, a fibrogenic cytokine involved in tissue repair. Conclusions: Significant overlapping demonstrated in the molecular mimicry of PBMCs and cardiomyocytes during preclinical and pathological stages of ALDOST implies that transcriptional signatures of PBMCs may serve as early noninvasive and novel sentinels predictive of impending pathological remodeling in HHD.

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U2 - 10.1016/j.jchf.2013.09.003

DO - 10.1016/j.jchf.2013.09.003

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JO - JACC: Heart Failure

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SN - 2213-1779

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