Molecular remodeling of ion channels, exchangers and pumps in atrial and ventricular myocytes in ischemic cardiomyopathy

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 Ca²⁺ 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.