title: Gene Expression Profiles of Peripheral Blood Mononuclear Cells Reveal Transcriptional Signatures as Novel Biomarkers for Cardiac Remodeling in Rats with Aldosteronism and Hypertensive Heart Disease.
abstract: OBJECTIVE
  In searching for a noninvasive surrogate tissue having mimicry with the prooxidant/-proinflammatory hypertensive heart disease (HHD) phenotype, we turned to peripheral blood mononuclear cells (PBMC). We tested whether iterations in [Ca2+]i, [Zn2+]iand oxidative stress in cardiomyocytes and PBMC would complement each other eliciting similar shifts in gene expression profiles in these tissues demonstrable during preclinical (wk 1) and pathologic (wk 4) stages of aldosterone/salt treatment (ALDOST).
  
  
  BACKGROUND
  Inappropriate neurohormonal activation contributes to pathologic remodeling of myocardium in HHD associated with aldosteronism. In rats receiving chronic ALDOST, evidence of reparative fibrosis replacing necrotic cardiomyocytes and coronary vasculopathy appears at wk 4 associated with the induction of oxidative stress by mitochondria that overwhelms endogenous, largely Zn2+-based, antioxidant defenses. Biomarker-guided prediction of risk prior to the appearance of cardiac pathology would prove invaluable.
  
  
  METHODS
  In PBMC and cardiomyocytes, quantitation of cytoplasmic free Ca2+and Zn2+, H2O2and 8-iosprostane levels, as well as isolation of RNA and gene expression, together with statistical and clustering analyses, and confirmation of genes byin situhybridization and RT-PCR, were performed.
  
  
  RESULTS
  Compared to controls, at wk 1 and 4 ALDOST, we found comparable: increments in [Ca2+]i, [Zn2+]iand 8-isoprotane coupled to increased H2O2production in cardiac mitochondria and PBMC, together with the common networks of expression profiles dominated by genes involved in oxidative stress, inflammation and repair. These included three central Ingenuity pathway-linked genes: p38MAPK, a stress-responsive protein; NFκB, a redox-sensitive transcription factor and a proinflammatory cascade it regulates; and TGF-β1, a fibrogenic cytokine involved in tissue repair.
  
  
  CONCLUSIONS
  Significant overlapping demonstrated in the molecular mimicry of PBMC and cardiomyocytes during preclinical and pathologic stages of ALDOST implicates that transcriptional signatures of PBMC may serve as early noninvasive and novel sentinels predictive of impending pathologic remodeling in HHD.
authors.affiliation: Division of Endocrinology, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Ivan C
authors.initials: IC
authors.lastname: Gerling
authors.affiliation: Department of Obstetrics and Gynecology, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Ahokas
authors.affiliation: Division of Cardiovascular Diseases, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: German
authors.initials: G
authors.lastname: Kamalov
authors.affiliation: Division of Cardiovascular Diseases, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Wenyuan
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Division of Cardiovascular Diseases, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Syamal K
authors.initials: SK
authors.lastname: Bhattacharya
authors.affiliation: Division of Cardiovascular Diseases, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Yao
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Division of Cardiovascular Diseases, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Karl T
authors.initials: KT
authors.lastname: Weber
keywords: aldosteronism; calcium; cardiomyocytes; gene chip array; oxidative stress; peripheral blood mononuclear cells; zinc