Alterations of cardiac protein kinases in cyclic nucleotide-dependent signaling pathways in human ischemic heart failure

Impaired protein kinase signaling is a hallmark of ischemic heart disease (IHD). Limited treatment options are available due to inadequate understanding of the pathological mechanisms. Identification of the key kinases in the pathogenesis of IHD with an effort to find potential therapeutic strategies is of high importance. Cardiac kinase activity in end-stage human IHD left ventricles (LVs) and the alteration in related signaling pathways were investigated by kinomics, transcriptomics, and proteomics, and by integration of the multi-omics datasets. Protein kinase A (PKA) and protein kinase G (PKG) ranked on top in the activity shift among the cardiac kinases. In the IHD LVs, PKA activity decreased markedly compared with that of controls (62% reduction, p=0.0034) whereas PKG activity remained stable although the amount of PKG protein increased remarkably (65%, p=0.003). mRNA levels of adenylate cyclases (ADCY 1, 3, 5, 9) and cAMP-hydrolysing phosphodiesterases (PDE4A, PDE4D) decreased significantly, while no statistically significant alterations were observed in that of PKGs (PRKG1 and PRKG2) and guanylate cyclases (GUCYs). mRNA level of CNP decreased remarkably whereas those of BNP, ANP and nyprilysin increased significantly in the IHD LVs. Proteomics analysis uncovered a significant reduction in proteins of ‘Energy metabolism’ and ‘Muscle contraction’ in the patients. Multi-omics integration highlighted intracellular signaling by second messengers as the top enriched Reactome pathway. The deficiency in cAMP/PKA signaling pathways is strongly implicated in the pathogenesis of IHD. Natriuretic peptide CNP could be a potential therapeutic target for the modulation of cGMP/PKG signaling. In an effort to identify novel cardiac kinases potentially involved in IHD and to expand our understanding of the cardiac kinome to search for potential therapeutic targets, we compared control and end-stage IHD human hearts by using an integrated kinomics, transcriptomics, and proteomics approach which allowed evaluation of the global profile changes.