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Key Signaling Pathways in the Cardiovascular System

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Abstract

The activity of the heart and vessels is permanently modulated in response to electrical, mechanical and chemical signals to maintain cardiovascular system homeostasis. Some effects are rapidly manifested (e.g. contraction after an electrical stimulus), while others are observed at long-term (e.g. hypertrophy resulting from gene expression modulation). In any case, an orchestrated set of events follows from receptor to intracellular messengers and effectors via complex signaling routes. These include neurohumoral signaling targeting G protein-coupled receptors (such as adrenaline, angiotensin II and endothelin-1 receptors), growth factor pathways initiated at tyrosine (including insulin, vascular endothelial growth factor and fibroblast growth factor) or serine/threonine kinase receptors (transforming growth factor-β) or even direct intracellular/nuclear pathways (triggered by calcium, nitric oxide or thyroid hormones). Herein, the signaling pathways taking place in cardiomyocytes, endothelial cells, vascular smooth muscle cells and fibroblasts, mainly involved in the regulation of cardiac contraction, vasorelaxation, mechanotransduction, cell survival and hypertrophy are described. Finally, the role of extracellular matrix in cardiac remodeling and fibrosis is reviewed.

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Abbreviations

AC:

Adenylate cyclase

AKAP:

A-kinase anchor protein

ALK:

Activin receptor-like kinases

Ang II:

Angiotensin II

ANP:

Atrial natriuretic peptide

β-AR:

β-adrenergic receptors

BNP:

B-type natriuretic peptide

Ca2+:

Calcium

CaM:

Calmodulin

CaMKII:

Ca2+/CaM-dependent protein kinase II

cAMP:

Cyclic adenosine monophosphate

cGMP:

Cyclic guanosine monophosphate

CREB:

cAMP-responsive element-binding protein

DAG:

Diacylglycerol

ECC:

Excitation-contraction coupling

ECM:

Extracellular matrix

ECs:

Endothelial cells

EGF:

Epidermal growth factor

eNOS:

Nitric oxide synthase, endothelial

ERK:

Extracellular signal-regulated protein kinase

ET-1:

Endothelin-1

ETA:

Endothelin receptor A

ETB:

Endothelin receptor B

ETC:

Excitation-transcription coupling

FAK:

Focal adhesion kinase

FGF:

Fibroblast growth factor

FGFR:

Fibroblast growth factor receptor

FoxO:

Forkhead box protein O

GC:

Guanylate cyclase

GPCRs:

G protein-coupled receptors

GSK3β:

Glycogen synthase kinase-3β

HB-EGF:

Heparin-binding EGF-like growth factor

HDAC:

Histone deacetylase

HIF-1α:

Hypoxia-inducible factor-1α

IGF:

Insulin-like growth factor

IP3:

Inositol 1,4,5-trisphosphate

IRS:

Insulin receptor substrate

JNK:

c-Jun N terminal kinase

LTCC:

Voltage-dependent L-type calcium channels

MLC:

Myosin light chain

MLCK:

Myosin light chain kinase

MLCP:

Myosin light chain phosphatase

MMP:

Matrix metalloproteinase

MyBP-C:

Myosin-binding protein C

NCX:

Sodium/calcium exchanger

NFAT:

Nuclear factor of activated T-cells

NF-κB:

Nuclear factor NF-kappa-B

NO:

Nitric oxide

NRG1:

Neuregulin 1

PDGF:

Platelet-derived growth factor

PDGFR:

PDGF receptor

PI-3K:

Phosphatidylinositol 3-kinase

PIP2:

Phosphatidylinositol 4,5-bisphosphate

PIP3:

Phosphatidylinositol 3,4,5-trisphosphate

PKA:

Protein kinase A

PKC:

Protein kinase C

PKG:

Protein kinase G

PLB:

Phospholamban

PLC:

Phospholipase C

RAAS:

Renin-angiotensin-aldosterone system

RyR:

Ryanodine receptor

SERCA:

Sarcoplasmic/endoplasmic reticulum calcium ATPase

SR:

Sarcoplasmic reticulum

STAT:

Signal transducer and activator of transcription

T3:

3,5,3′-triiodothyronine

T4:

3,5,3′,5′-tetraiodothyronine

TGF-β:

Transforming growth factor-β

TH:

Thyroid hormone

TR:

TH receptors

TβR:

TGF-β receptors

VEGF:

Vascular endothelial growth factor

VEGFR:

VEGF receptor

VSMCs:

Vascular smooth muscle cells

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Acknowledgments

Thanks are due to the Portuguese Foundation for Science and Technology (FCT), European Union, QREN, FEDER and COMPETE for the financial support for the UnIC (UID/IC/00051/2019), iBiMED (UIDB/04501/2020) and CIAFEL (UIDB/00617/2020) research units and the research projects DOCnet (NORTE-01-0145-FEDER-000003) and NETDIAMOND (POCI‐01‐0145‐FEDER‐016385) and the post-graduation student (grant number SFRH/BD/111633/2015 to F.T.).

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Authors and Affiliations

  1. Department of Surgery and Physiology, Cardiovascular R&D Center, Faculty of Medicine of the University of Porto, Porto, Portugal

    Fábio Trindade, Inês Falcão-Pires, Adelino Leite-Moreira, Daniel Moreira-Gonçalves & Rita Nogueira-Ferreira

  2. Department of Medical Sciences, iBiMED–Institute of Biomedicine, University of Aveiro, Aveiro, Portugal

    Fábio Trindade

  3. School of Kinesiology, Auburn University, Auburn, AL, USA

    Andreas Kavazis

  4. Department of Cardiothoracic Surgery, Centro Hospitalar Universitário São João, Porto, Portugal

    Adelino Leite-Moreira

  5. Faculty of Sport, CIAFEL, University of Porto, Porto, Portugal

    Daniel Moreira-Gonçalves

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  1. Fábio Trindade
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Correspondence to Fábio Trindade or Rita Nogueira-Ferreira .

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  1. Laboratory of Signal Transduction, Department of Medical Sciences, Institute of Biomedicine—iBiMED, University of Aveiro, Aveiro, Portugal

    Joana Vieira Silva

  2. Laboratory of Protein Phosphorylation and Proteomics, Department of Cellular and Molecular Medicine, Faculty of Medicine, KU Leuven, Leuven, Belgium

    Maria João Freitas

  3. Laboratory of Signal Transduction, Department of Medical Sciences, Institute of Biomedicine—iBiMED, University of Aveiro, Aveiro, Portugal

    Margarida Fardilha

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Trindade, F., Falcão-Pires, I., Kavazis, A., Leite-Moreira, A., Moreira-Gonçalves, D., Nogueira-Ferreira, R. (2020). Key Signaling Pathways in the Cardiovascular System. In: Silva, J.V., Freitas, M.J., Fardilha, M. (eds) Tissue-Specific Cell Signaling. Springer, Cham. https://doi.org/10.1007/978-3-030-44436-5_12

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