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 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+]i and 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+, H2O2 and 8-iosprostane levels, as well as isolation of RNA and gene expression, together with statistical and clustering analyses, and confirmation of genes by in situ hybridization and RT-PCR, were performed. Results Compared to controls, at wk 1 and 4 ALDOST, we found comparable: increments in [Ca2+]i, [Zn2+]i and 8-isoprotane coupled to increased H2O2 production 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.

Ribonucleic Acid Biomarkers for Heart Failure

“…The current study by Gerling et al 18 _ENREF_15_ENREF_15_ENREF_15 provides additional supportive data for this concept. While direct sampling of myocardium might offer advantages for biomarker application, using peripheral blood has obvious benefit in terms of broader application and generalizability of transcriptomic biomarkers as they emerge in cardiovascular medicine.…”

“…In the current issue of JACC Heart Failure, Gerling et al 18 address this important issue by comparing the global mRNA expression profiles from heart tissue to peripheral blood mononuclear cells (PBMCs) in an aldosterone rat model of heart failure. Their findings in gene expression and molecular pathway analysis supported a correlation between the blood and heart transcriptomics.…”

Long Noncoding RNAs in Patients With Acute Myocardial Infarction

“…20 In addition, RNA expression profiles of blood cells and cardiomyocytes share common features in response to aldosterone treatment in hypertensive rats and are associated with pathological remodeling. 21 The rationale for the selection of the 5 lncRNAs investigated in this study is as follows. aHIF, a natural antisense transcript of HIF1α, is overexpressed in the failing heart.…”

Putative biological predictors of treatment response in bipolar disorders

“…Peripheral biomarkers are an excellent alternative to traditional tissue biopsy-derived RNA and are the most logical proxy for the brain. Peripheral gene expression profiling has been successfully used to examine treatment response for a variety of genetically complex medical disorders [221][222][223][224][225][226][227][228][229][230]. Sugawara et al studied gene expression changes induced by lithium and valproate in order to elucidate the common molecular effect of therapeutic concentrations of these drugs on lymphoblastoid cell cultures derived from healthy subjects.…”