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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE203160 | GEO | 2022/07/06

REPOSITORIES: GEO

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Project description:The second messenger cAMP acts via protein kinase A (PKA) to induce apoptosis by mechanisms that are poorly understood. Here, we assessed a role for mitochondria and analyzed gene expression in cAMP/PKA-promoted apoptosis by comparing wild-type (WT) S49 lymphoma cells and the S49 variant, D- (cAMP-deathless), which lacks cAMP-promoted apoptosis but has wild-type levels of PKA activity and cAMP-promoted G1 growth arrest. Treatment of WT, but not D-, S49 cells with 8-CPT-cAMP for 24 h induced loss of mitochondrial membrane potential, mitochondrial release of cytochrome c and Smac and increase in caspase-3 activity. Gene expression analysis (using Affymetrix 430 2.0 Arrays) revealed that WT and D- cells incubated with 8-CPT-cAMP have similar, but non-identical, extents of cAMP-regulated gene expression at 2h (~800 transcripts) and 6h (~1000 transcripts) (|Fold|>2, P<0.06); by contrast, at 24h ~2500 and ~1100 transcripts were changed in WT and D- cells, respectively. Using an approach that combined regression analysis, clustering and functional annotation to identify transcripts that showed differential expression between WT and D- cells, we found differences in cAMP-mediated regulation of mRNAs involved in transcriptional repression, apoptosis, the cell cycle, RNA splicing, Golgi and lysosomes. The 2 cell lines differed in CREB phosphorylation and expression of the transcriptional inhibitor Icer and in cAMP-regulated expression of genes in the Inhibitor of apoptosis (IAP) and Bcl families. The findings indicate that cAMP/PKA-promoted apoptosis of lymphoid cells occurs via mitochondrial-mediated events and imply that such apoptosis involves gene networks in multiple biochemical pathways. Experiment Overall Design: S49 D- cells were treated with 8-CPT-cAMP over the course of 24 hours. Cells were prepared for hybridization to microarrays at times 0-untreated, 2h, 6h, and 24h after treatment with 8-CPT-cAMP. Experimental replicates were as follows n=4 for time 0 and n=3 for 2, 6, and 24h post treatment.

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

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