Alterations of Cardiac Protein Kinases in Cyclic Nucleotide-Dependent Signaling Pathways in Human Ischemic Heart Failure

Chunguang Wang; Juuso H Taskinen; Heli Segersvärd; Katariina Immonen; Riikka Kosonen; Johanna M Tolva; Mikko I Mäyränpää; Petri T Kovanen; Vesa M Olkkonen; Juha Sinisalo; Mika Laine; Ilkka Tikkanen; Päivi Lakkisto

doi:10.3389/fcvm.2022.919355

Alterations of Cardiac Protein Kinases in Cyclic Nucleotide-Dependent Signaling Pathways in Human Ischemic Heart Failure

Front Cardiovasc Med. 2022 Jun 17:9:919355. doi: 10.3389/fcvm.2022.919355. eCollection 2022.

Authors

Chunguang Wang¹, Juuso H Taskinen¹, Heli Segersvärd¹, Katariina Immonen¹, Riikka Kosonen¹, Johanna M Tolva², Mikko I Mäyränpää³, Petri T Kovanen⁴, Vesa M Olkkonen^{1

5}, Juha Sinisalo⁶, Mika Laine^{1

6}, Ilkka Tikkanen^{1

7}, Päivi Lakkisto^{1

8}

Affiliations

¹ Minerva Foundation Institute for Medical Research, Biomedicum Helsinki 2 U, Helsinki, Finland.
² Transplantation Laboratory, Department of Pathology, University of Helsinki, Helsinki, Finland.
³ Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
⁴ Atherosclerosis Research Laboratory, Wihuri Research Institute, Helsinki, Finland.
⁵ Department of Anatomy, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
⁶ Heart and Lung Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
⁷ Abdominal Center, Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
⁸ Clinical Chemistry and Hematology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Abstract

Objectives: Impaired protein kinase signaling is a hallmark of ischemic heart disease (IHD). Inadequate understanding of the pathological mechanisms limits the development of therapeutic approaches. We aimed to identify the key cardiac kinases and signaling pathways in patients with IHD with an effort to discover potential therapeutic strategies.

Methods: Cardiac kinase activity in IHD left ventricle (LV) and the related signaling pathways were investigated by kinomics, transcriptomics, proteomics, and integrated multi-omics approach.

Results: 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, although no statistically significant alterations were observed in that of PKGs (PRKG1 and PRKG2) and guanylate cyclases (GUCYs). The gene expression of natriuretic peptide CNP decreased remarkably, whereas those of BNP, ANP, and neprilysin increased significantly in the IHD LVs. Proteomics analysis revealed a significant reduction in protein levels of "Energy metabolism" and "Muscle contraction" in the patients. Multi-omics integration highlighted intracellular signaling by second messengers as the top enriched Reactome pathway.

Conclusion: The deficiency in cAMP/PKA signaling pathway is strongly implicated in the pathogenesis of IHD. Natriuretic peptide CNP could be a potential therapeutic target for the modulation of cGMP/PKG signaling.

Keywords: cAMP-dependent protein kinase; cGMP-dependent protein kinase; cardiac kinome; ischemic heart disease; ischemic heart failure; natriuretic peptide; second messenger intracellular signaling.