Sex- and age-dependent human transcriptome variability: Implications for chronic heart failure

Abstract

Heart failure (HF) is the end result of progressive and diverse biological adaptations within the diseased myocardium. We used cDNA microarrays and quantitative PCR to examine the transcriptomes of 38 left ventricles from failing and nonfailing human myocardium. After identification of a pool of putative HF-responsive candidate genes by microarrays on seven nonfailing and eight failing hearts, we used quantitative PCR and a general linear statistical model in a larger sample set (n ‫؍‬ 34) to validate and examine the role of contributing biological variables (age and sex). We find that most HF-candidate genes (transcription factors, Cebpb, Npat; signaling molecules, Map2k3, Map4k5; extracellular matrix proteins, Lum, Cola1; and metabolic enzymes, Mars) demonstrated significant changes in gene expression; however, the majority of differences among samples depended on variables such as sex and age, and not on HF alone. Some HF-responsive gene products also demonstrated highly significant changes in expression as a function of age and͞or sex, but independent of HF (Ngp1, Cd163, and Npat). These results emphasize the need to account for biological variables (HF, sex and age interactions) to elucidate genomic correlates that trigger molecular pathways responsible for the progression of HF syndromes.

The Pro-angiogenic Cytokine Pleiotrophin Potentiates Cardiomyocyte Apoptosis through Inhibition of Endogenous AKT/PKB Activity

“…Human ventricular myocardial samples were obtained from 18 male patients with severe heart failure secondary to idiopathic dilated cardiomyopathy or ischemic heart disease and from 18 unused male donor hearts (25,28). The average ages of the two groups were 50.2 Ϯ 16.0 and 53.8 Ϯ 19.1 years.…”

“…Real Time PCR, Western Blotting, and ELISA-Total RNA was reverse-transcribed, and PCRs were run in the presence of SYBR green (28 Adenovirus and Adenoviral Infection-A recombinant replication-defective adenovirus encoding a hemagglutinin (HA) epitope-tagged constitutively activated AKT-1 and a control virus expressing no gene product (Ad/CMV/DEST-null) were constructed by recombination cloning from a plasmid encoding myr-AKT1-HA (gift of T. Francke, Columbia University) into pAd/CMV/V5-DEST vector (Invitrogen) to generate pAd/CMV/DEST-myrAkt1-HA. The viruses were commercially amplified, purified, and titered (Vector Laboratories).…”

The Effects of Biological Sex and Diet on the Development of Heart Failure

“…85 In the study by Boheler et al, 85 11 genes in failing hearts vary by sex, including calponin 1, insulin growth factor-binding protein 4, mitogen-activated protein 4 kinase 5, and cyclin-dependent kinase inhibitor. The directional change in gene expression depends on sex.…”

Relations of Plasma Matrix Metalloproteinase-9 to Clinical Cardiovascular Risk Factors and Echocardiographic Left Ventricular Measures

“…It is equally conceivable that molecular differences exist between sexes in the LV remodeling process. 44,45 Investigators have reported sexrelated differences in remodeling at the cardiomyocyte level, influenced partly by MMP activation. 46 In the early phase of volume overload, male animals have smaller myocyte lengths as the result of amitotic division of binucleate cardiomyocytes, whereas female animals have increased length of myocytes.…”