Molecular Mechanisms in Genetic Aortopathy–Signaling Pathways and Potential Interventions
Abstract
:1. Background
2. Cell Function in Normal and Aneurysmal Aorta
3. TGF-β Signaling
3.1. Regulation of TGF-β Signaling
3.2. TGF-β and VSMC
3.3. TGF-β and EC
4. WNT Signaling
4.1. Regulation of WNT Signaling
4.2. WNT and VSMC
4.3. WNT and EC
5. PI3K/AKT Signaling
5.1. Regulation of PI3K/AKT Signaling
5.2. PI3K/AKT and VSMC
5.3. PI3K/AKT and EC
6. NOTCH Signaling
6.1. Regulation of NOTCH Signaling
6.2. NOTCH and VSMC
6.3. NOTCH and EC
7. Angiotensin Signaling
7.1. Regulation of ANG II Signaling
7.2. Angiotensin II and VSMC
7.3. Angiotensin II and EC
8. Interactions between Pathways
Summary of Pathway Interactions
9. Role of Signaling Pathways in Pathogenesis of TAA
9.1. TGF-β and TAA
9.2. WNT and TAA
9.3. PI3K/AKT and TAA
9.4. NOTCH and TAA
9.5. Angiotensin II and TAA
10. Potential Therapeutic Interventions
10.1. TGF-β/BMP/SMAD Pathway
10.2. WNT Pathway
10.3. PI3K/AKT Pathway
10.4. NOTCH Pathway
10.5. Angiotensin II Pathway
10.6. Application of Pathway Therapeutics to TAA
11. Conclusions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
ACVRL1 | activin A receptor like type 1 |
ADAM17 | A disintegrin and metalloproteinase 17 |
ADNP | activity dependent neuroprotector homeobox transcription factor |
ALK | ALK receptor tyrosine kinase |
AKT | protein kinase B |
ANG | Angiotensin |
AP-1 | activator protein 1 |
AT1(2)R | angiotensin type 1 (2) receptor |
BAD | BCL2 associated agonist of cell death |
BAEC | bovine aortic endothelial cell |
BAMBI | BMP and activin membrane bound inhibitor |
BAV | bicuspid aortic valve |
BMP | bone morphogenic protein |
CADASIL | cerebral autosomal dominant arteriopathy with sub-cortical infarcts and leukoencephalopathy |
CAMKII | calcium/calmodulin dependent protein kinase 2 |
CCND1 | cyclinD1 |
COX2 | cyclooxygenase 2 |
CREB | cAMP response element binding protein transcription factor |
CSL/RBPJ | recombination binding protein for immunoglobulin Kappa J |
CTGF | connective tissue growth factor |
DKK | Dickkopf WNT signaling pathway inhibitor |
DLL | delta like canonical Notch ligand |
DVL1 | disheveled segment polarity protein 1 |
EC | endothelial cell |
ECM | extracellular matrix |
EGFL7 | epidermal growth factor like domain multiple 7 |
EGFR | epidermal growth factor receptor |
ERK | extracellular signal-regulated kinase |
FN1 | fibronectin 1 |
FOXO | forkhead box gene group O |
FZD | frizzled receptor |
GSK-3β | glycogen synthase kinase 3 beta |
H2O2 | hydrogen peroxide |
HERP | homocysteine inducible ER protein |
HES | hairy and enhancer of split-1 transcription factor |
HEY | hairy ears Y linked transcription factor |
HAEC | human aortic endothelial cell |
HUVEC | human umbilical vein endothelial cell |
hTAA | heritable thoracic aortic aneurysm |
IGFBP | insulin-like growth factor binding protein |
IGF-1R | insulin-like growth factor 1 receptor |
IL-8 | interleukin 8 |
JAK2 | janus kinase 2 |
JNK | c-Jun N-terminal kinase |
LDL | low density lipoprotein |
LDS | Loeys-Dietz syndrome |
LEF | lymphoid enhancer binding factor transcriptional activator |
LRP | low-density lipoprotein receptor-related protein |
LTBP | latent TGFbeta binding protein |
MAGP-2 | microfibril associated glycoprotein 2 |
MAML | mastermind-like protein 1 |
MAPK | mitogen activated protein kinase |
MAS | Mas-related G protein couple receptor |
MDM2 | MDM2 proto-oncogene E3 ubiquitin protein ligase |
MEF2 | myocyte enhancer factor 2C |
MEK | MAPK/ERK kinase |
MFS | Marfan syndrome |
MK2 | mitogen-activated protein kinase-activated protein kinase 2 |
MMP | matrix metalloproteinase |
mTOR | mammalian target of rapamycin |
NADPH | nicotinamide adenine dinucleotide phosphate |
NEDD4 | neural precursor cell expressed developmentally downregulated protein 4 |
NF-κB | nuclear factor kappa B |
NICD | Notch intracellular domain |
NO | nitric oxide |
NOS | nitric oxide synthase |
NOTCH | Notch receptor protein |
NOTUM | Notum palmitoleoyl-protein-carboxylesterase |
NOX | NADPH oxidase |
PAI-1 | plasminogen activator inhibitor type-1 |
PDGF | platelet-derived growth factor |
PI3K | phosphoinositide 3-kinase |
PIP3 | phosphatidyinositol (3,4,5)-triphosphate |
PKC-δ | protein kinase C gamma |
PLA(C) | phospholipase A (C) |
PTEN | phosphatase and tensin homolog |
p38 | p38 mitogen-activated protein kinase |
ROCK | Rho associated coiled-coil containing protein kinase |
ROS | reactive oxygen species |
RTK | receptor tyrosine kinase |
RUNX | RUNX family transcription factor |
SARA | SMAD anchor for receptor activation |
SKI | SKI proto-oncogene |
SM22α | smooth muscle protein 22-alpha |
SMA | smooth muscle actin |
SMAD | small mothers against decapentaplegic |
SMURF | SMAD ubiquitination regulatory factor |
SNON | SKI-like proto-oncogene |
SOD | superoxide dismutase |
SOST | Sclerostin |
SP1 | specificity protein 1 transcription factor |
SPRY1 | sprouty RTK signaling antagonist 1 |
TAA | thoracic aortic aneurysm |
TAV | tricuspid aortic valve |
TCF | T-cell factor enhancer binding factor transcriptional activator |
TGF-β | transforming growth factor β |
TGFBR | transforming growth factor beta receptor |
TIMP1 | tissue inhibitor of metalloproteinases 1 |
TNF-α | tumor necrosis factor alpha |
TRABD2B | TraB domain containing 2B |
VCAM-1 | vascular cell adhesion molecule 1 |
VCAN | Versican |
VEGF | vascular endothelial growth factor |
VSMC | vascular smooth muscle cells |
WIF-1 | WNT inhibitory factor 1 |
WISP | WNT1 inducible signaling pathway protein |
WNT | wingless-related integration site |
ZNRF | zinc and ring finger ubiquitin protein ligands |
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Vascular Smooth Muscle Cell | ||||||
Pathway | Promote contractile phenotype and survival | Promote proliferative response | Promote synthetic phenotype, apoptosis, proliferation, and migration | |||
Direct | Indirect | Direct | Indirect | Direct | Indirect | |
TGF-β | + | + | + | + | ||
WNT | + | + | + | |||
PI3K/AK | + | + | + | |||
NOTCH | + | + | + | + | ||
ANGII | + | + | ||||
Endothelial Cell | ||||||
Pathway | Promote survival and EC quiescence | Promote proliferation and migration | Promote EC dysregulation, apoptosis, and inflammation | |||
Direct | Indirect | Direct | Indirect | Direct | Indirect | |
TGF-β | + | + | + | |||
WNT | + | + | + | + | + | |
PI3K/AK | + | + | + | + | ||
NOTCH | + | |||||
ANGII | + | + | + |
Pathway | Experimental | Human |
---|---|---|
TGF-ß/SMAD | Murine Murine MFS/LDS | Isolated aortic VSMC Proteomics Clinical Genetics |
Angiotensin II | Murine Murine MFS | Clinical |
PI3K/AKT | Murine Murine MFS | Isolated aortic VSMC TAA tissue |
WNT | Murine Murine MFS Aortic interstitial cells | Cardiac fibroblasts Isolated EC Isolated aortic VSMC GWAS TAA tissue |
NOTCH | Murine Murine MFS | Isolated EC Isolated aortic VSMC Proteomics TAA tissue Clinical Genetics |
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Dong, C.X.; Malecki, C.; Robertson, E.; Hambly, B.; Jeremy, R. Molecular Mechanisms in Genetic Aortopathy–Signaling Pathways and Potential Interventions. Int. J. Mol. Sci. 2023, 24, 1795. https://doi.org/10.3390/ijms24021795
Dong CX, Malecki C, Robertson E, Hambly B, Jeremy R. Molecular Mechanisms in Genetic Aortopathy–Signaling Pathways and Potential Interventions. International Journal of Molecular Sciences. 2023; 24(2):1795. https://doi.org/10.3390/ijms24021795
Chicago/Turabian StyleDong, Charlotte Xue, Cassandra Malecki, Elizabeth Robertson, Brett Hambly, and Richmond Jeremy. 2023. "Molecular Mechanisms in Genetic Aortopathy–Signaling Pathways and Potential Interventions" International Journal of Molecular Sciences 24, no. 2: 1795. https://doi.org/10.3390/ijms24021795