Clin Res Cardiol (2022).

Distinct regulation of transcriptome and proteome in human diabetic cardiomyopathy and diabetic heart failure
J. Gollmer1, L. Potter2, I. Vosko1, T. Tomin3, R. Birner-Gruenberger3, D. von Lewinski1, S. Sedej1, D. Scherr1, A. Wende2, P. P. Rainer1, A. Zirlik1, H. Bugger1
1Department of Cardiology, Medical University of Graz, Graz, Österreich; 2Department of Pathology, Division of Molecular and Cellular Pathology,, University of Alabama at Birmingham, Birmingham, US; 3Instrumental and Imaging Analytical Chemistry, Institute of Chemical Technologies and Analytics TU Wien, Wien, AT;
Independent of ischemic heart disease (IHD), Type 2 diabetes mellitus (T2DM) may induce cardiac hypertrophy and subclinical impairment in cardiac function, also termed diabetic cardiomyopathy (DbCM), which may progress to heart failure with preserved ejection fraction. In addition, T2DM may also promote the development of heart failure with reduced ejection fraction (DbHF), in particular in subjects with IHD but via mechanisms that are independent of IHD. Since underlying mechanisms of both disease entities remain poorly understood, we aimed to identify candidate mechanisms using unbiased transcriptome and proteome analysis. Left ventricular samples of 15 non-diabetic patients with normal ejection fraction (EF; 64±7%) and no history of IHD (=controls), 8 patients with T2DM, normal EF (63±5%) and no history of IHD (referred to as DbCM), and 7 patients with T2DM, reduced EF (26±9%) and IHD (referred to as DbHF) were collected and subjected to RNA sequencing and comparative proteomics using label-free LC-MS/MS. RNA sequencing revealed 1795 differentially regulated genes in DbHF vs. controls, 527 differentially regulated genes in DbCM vs. controls, and only 128 genes commonly regulated in DbCM and DbHF. Hierarchical cluster analysis revealed clear signatures to discriminate DbHF samples from controls, whereas DbCM samples showed only discrete signatures to discriminate them from controls. Gene ontology enrichment analysis identified pathways associated with inflammation and immunity as major regulated pathways in DbHF samples, whereas extracellular matrix remodeling and cellular growth were the most regulated pathways in DbCM samples. Our proteomic approach detected a total of 1169 proteins. In DbHF samples, 146 proteins were differentially regulated, whereas only 66 proteins were regulated in DbCM samples. Pathways involved in oxidative stress and acute inflammatory response were upregulated, and energy metabolic pathways (ATP synthesis, oxidative phosphorylation) were downregulated in DbHF samples. In DbCM samples, pathways involved in structural remodeling, cardiomyocyte proliferation, and mechanotransduction were enriched while only mild effects were observed on pathways of energy metabolism. In conclusion, we identified several candidate mechanisms that may underlie human DbCM and DbHF and validate some of the findings from animal models of T2DM. The regulation of distinct molecular pathways in DbCM and DbHF samples suggests that DbHF and DbCM may be distinct disease entities rather than being a continuum were DbCM precedes the development of systolic heart failure.