title: Molecular remodeling of ion channels, exchangers and pumps in atrial and ventricular myocytes in ischemic cardiomyopathy.
abstract: Existing molecular knowledge base of cardiovascular diseases is rudimentary because of lack of specific attribution to cell type and function. The aim of this study was to investigate cell-specific molecular remodeling in human atrial and ventricular myocytes associated with ischemic cardiomyopathy. Our strategy combines two technological innovations, laser-capture microdissection of identified cardiac cells in selected anatomical regions of the heart and splice microarray of a narrow catalog of the functionally most important genes regulating ion homeostasis. We focused on expression of a principal family of genes coding for ion channels, exchangers and pumps (CE&P genes) that are involved in electrical, mechanical and signaling functions of the heart and constitute the most utilized drug targets. We found that (1) CE&P genes remodel in a cell-specific manner: ischemic cardiomyopathy affected 63 CE&P genes in ventricular myocytes and 12 essentially different genes in atrial myocytes. (2) Only few of the identified CE&P genes were previously linked to human cardiac disfunctions. (3) The ischemia-affected CE&P genes include nuclear chloride channels, adrenoceptors, cyclic nucleotide-gated channels, auxiliary subunits of Na(+), K(+) and Ca(2+) channels, and cell-surface CE&Ps. (4) In both atrial and ventricular myocytes ischemic cardiomyopathy reduced expression of CACNG7 and induced overexpression of FXYD1, the gene crucial for Na(+) and K(+) homeostasis. Thus, our cell-specific molecular profiling defined new landmarks for correct molecular modeling of ischemic cardiomyopathy and development of underlying targeted therapies.
authors.affiliation: National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Naomi
authors.initials: N
authors.lastname: Gronich
authors.forename: Azad
authors.initials: A
authors.lastname: Kumar
authors.forename: Yuwei
authors.initials: Y
authors.lastname: Zhang
authors.forename: Igor R
authors.initials: IR
authors.lastname: Efimov
authors.forename: Nikolai M
authors.initials: NM
authors.lastname: Soldatov
mesh_terms: D000328:Adult; D000368:Aged; D001692:Biological Transport; D009202:Cardiomyopathies / Q000209:etiology / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D006325:Heart Atria / Q000737:chemistry; D006352:Heart Ventricles / Q000737:chemistry; D006801:Humans; D007473:Ion Channels / Q000235:genetics*; D016623:Ion Pumps / Q000235:genetics*; D008297:Male; D042282:Microdissection / Q000379:methods; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000150:complications / Q000235:genetics*; D032383:Myocytes, Cardiac / Q000737:chemistry*; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000032:analysis
chemical_list: D007473:Ion Channels; D016623:Ion Pumps; D012333:RNA, Messenger