Roles of Integrin in Cardiovascular Diseases: From Basic Research to Clinical Implications
Abstract
:1. Introduction
2. Potential Effects of Integrins in CVDs
2.1. Atherosclerosis
2.1.1. Integrins That Bind to RGD Receptors
2.1.2. Integrins That Bind to Laminin Receptors
2.1.3. Integrins That Bind to Leukocyte-Specific Receptors
2.2. Cardiac Fibrosis
2.2.1. αV Integrins
2.2.2. β1 Integrins
2.2.3. Other Integrins
2.3. Arrhythmias
2.4. Hypertension
3. Integrin-Based Therapy
3.1. Integrin Antagonists, Antibodies, and Inhibitors
3.2. Nanotherapy
4. Discussion
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Disease | Cell Types | Integrin | ECM | Main Functions | Effects of Signal Modulation | Reference |
---|---|---|---|---|---|---|
AS | VEC | α5β1 | ANX2 Ox-LDL | Promotes the translocation of α5β1 integrins to lipid rafts and activates the endothelial inflammatory pathway | Foam cell deposition Vascular endothelial inflammation | [35,36] |
COMP | Inhibits the activation of α5β1 integrins | Alleviates the vascular endothelial inflammation | [14] | |||
Gal-3 | Activates the β1 integrin/RhoA/JNK signaling pathway and exacerbates ox-LDL-mediated vascular endothelial injury | Foam cell deposition Vascular endothelial inflammation | [37] | |||
β4 | Activates the Src/NF-kB signaling pathway and promotes the expression of endothelial inflammatory factors | Vascular endothelial inflammation | [38] | |||
α6β1 | CCN1 | Activates NF-kB and forms a positive feedback loop with CCN1 and α6β1 integrins | Oxidative stress Vascular endothelial inflammation | [39] | ||
VSMC | α5β1 | MFG-E8 | Promotes the MMP2 expression and activates the TGF-β1/Smad2/3 signaling pathway | VSMC calcification Vascular wall calcification | [15] | |
α-SMA | Mediates vascular tone dysregulation and VSMC migration | Vasoconstrictive dysfunction | [40] | |||
β3 | Thrombin | Interacts with CD47 and mediates VSMC migration and proliferation | Vascular wall thickening and vascular restenosis | [41] | ||
Immune cell | αMβ2 | ICAM-1 | Induces the adhesion and extravasation of immune cells on the vascular endothelium | Vascular endothelial inflammation | [16] | |
Gal-9 | Activates and promotes the differentiation of monocytes to macrophages | Vascular endothelial inflammation Atherosclerotic plaque formation | [42] | |||
αDβ2 | DHA CEP | Promotes M1 macrophage accumulation in ECM | Vascular endothelial inflammation Atherosclerotic plaque formation | [43] | ||
αVβ5 | Cadherin ICAM-1 E-selectin | Promotes fibronectin expression and macrophage migration | Vascular endothelial inflammation Atherosclerotic plaque formation | [44] | ||
PPARγ | Promotes M2 macrophage polarization and the expression of anti-inflammatory factors | Attenuates AS and promotes tissue repair | [45] | |||
Omentin-1 | Induces the PI3K/Akt signaling pathway and AMPK phosphorylation | Promotes plaque stability | [46] | |||
OPN | Attenuates vascular calcification | Promotes positive ischemic neovascularization | [47] | |||
α4 | FABP4 | Induces macrophage adhesion | Vascular endothelial inflammation Atherosclerotic plaque formation | [48,49] | ||
α5β1 | EphA2 | Promotes immunocyte adhesion | [50] | |||
β2 | E-selectin ICAM-1 | Activates the Syk/Src signaling pathway and then promotes the calcium reflux of neutrophils | [51] | |||
Promotes eosinophil adhesion | [52] | |||||
PAD4 | Promotes neutrophil adhesion | [53] | ||||
Platelet | αIIbβ3 | Fibrinogen | Activates Rho GTPase RAC1 and RhoA, thereby promoting cytoskeletal reorganization | Thrombus formation | [54] | |
GNE495 PF 06260933 | Inhibits the pathogenic roles of αIIbβ3 integrins | Inhibits platelet aggregation and clot retraction | [55] | |||
αVβ3 | Fibronectin | Promotes platelet adhesion and aggregation | Thrombus formation | [56,57] |
Disease | Cell Types | Integrin | ECM | Main Functions | Effects of Signal Modulation | Reference |
---|---|---|---|---|---|---|
Cardiac fibrosis | Cardiac fibroblast | αVβ5 αVβ3 | Latent TGF-β | Activates the TGF-β1/Smad2/3/α-SMA signaling pathway and promotes collagen synthesis | Cardiac fibroblast transdifferentiation and collagen deposition | [76,77] |
Activates the FAK/c-Src/NF-kB signaling pathway and promotes collagen synthesis | [78] | |||||
αVβ1 | Latent TGF-β | Activates the FAK/Akt/mTOR and TGF-β/Smad2/3/α-SMA signaling pathways | [79] | |||
Fibronectin | [80] | |||||
CD63 | Promotes the translocation of Smad2/3 and β-catenin, thereby promoting collagen synthesis | [80] | ||||
α2β1 | Collagen | Activates FAK and Src | Attenuates collagen deposition | [81] | ||
Activates PP2A/PTEN signaling pathway and then inhibits Akt and α-SMA expression | [82] |
Disease | Cell Types | Integrin | ECM | Main Functions | Effects of Signal Modulation | Reference |
---|---|---|---|---|---|---|
Arrhythmias | Cardiomyocyte | β1 | Activates the ILK/Akt/Cx43/PI3K/Akt signaling pathway | Diminishes cardiac remodeling and attenuates arrhythmias | [111,112,113] | |
Activates the talin/Vcl/ZO-1/Cx43 signaling pathway, thereby promoting Cx43 stability | Stabilizes the myocardial electrical signal Attenuates arrhythmias | [17] | ||||
Fibronectin | Promotes β1 integrin degradation and inhibits RyR2 phosphorylation | Myocardial electrical signal dysfunction | [114] | |||
α5 | Fibronectin | Promotes ECM collagen deposition | Myocardial damage Cytoskeletal remodeling | [115] |
Disease | Cell Types | Integrin | ECM | Main Functions | Effects of Signal Modulation | Reference |
---|---|---|---|---|---|---|
Hypertension | PASMC | β3 | MMP8 | Activates the FAK/YAP/TAZ signaling pathway and promotes PASMC proliferation | Vascular remodeling | [119] |
αVβ3 | Hypoxia | Activates the Pyk2/ERK/NF-kB/H2O2 signaling pathway, thereby reducing PPARγ expression and promoting PASMC proliferation | [120] | |||
Activates the OPG/FAK/Akt signaling pathway and promotes PASMC proliferation | [61,121] | |||||
OPN | Activates the ERK1/2/Akt signaling pathway and promotes PASMC proliferation | [122] | ||||
β5 | PDGF-BB | Activates the Ubal protein/Ube2n/Mdm2/ACE2 and miR-96-5p/mTOR signaling pathways, thereby promoting PASMC proliferation | [123,124] |
Category | Related Integrin | Functions | Implication in CVD | Agents in Clinics | Reference |
---|---|---|---|---|---|
Integrin antagonists and antibodies | αIIbβ3 | Inhibits platelet aggregation with fibrinogen and clot retraction | Inhibits thrombosis | Abciximab, Eptifibatide, Tirofiban | [18,133,134,135,136,137] |
α2β1 | Inhibits the adhesion of platelets to collagen Inhibits the expression of collagen and collagenase genes Inhibits the phenotypic plasticity of VSMC | Inhibits thrombosis and plaque formation | Vatelizumab | [134,138] | |
α4β1 | Inhibits the phenotypic plasticity of VSMC | Inhibits plaque formation and platelet aggregation | Natalzumab, AJM300 | [139,140,141,142] | |
α5β1 | Inhibits the phenotypic plasticity of VSMC | Inhibits plaque formation and platelet aggregation | Volociximab, ATN61 | [143,144,145] | |
α9β1 | Inhibits the phenotypic plasticity of VSMC | Inhibits plaque formation and platelet aggregation | ASP5094 | [146,147] | |
αVβ3 | Inhibits the phenotypic plasticity of VSMC | Inhibits plaque formation and platelet aggregation | LM609, Abciximab (c7E3Fab; ReoPro), Vitaxin, Inttumumab, | [143,148,149,150,151,152] | |
αVβ5 | Inhibits the phenotypic plasticity of VSMC | Inhibits plaque formation and platelet aggregation | LM609 Inttumumab | [151,153] | |
β2 | Inhibits leukocyte extravasation | Reduces inflammatory tissue damage | [8] | ||
β3 | Inhibits NF-κB nuclear translocation Downregulates VEGF expression | Inhibits angiogenesis | Kallistatin | [154] | |
Nanotherapy | αIIbβ3 | Surfaces with RGD peptide; Loading thrombolytic drugs | Thrombolysis | [19,155] | |
αIIbβ3 | Contains M3mP6 or M3mp13 Inhibits signaling pathways of αIIbβ3 integrins | Inhibits thrombosis | [23,129,156] | ||
ανβ3 | Contains cRGDfK peptide | [130] | |||
αVβ3 | Releases RAP | Inhibits local inflammation | RAP@T/R NPs | [157] | |
α4β1 | MMM NPs | [128] |
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Zhang, S.; Zhang, Q.; Lu, Y.; Chen, J.; Liu, J.; Li, Z.; Xie, Z. Roles of Integrin in Cardiovascular Diseases: From Basic Research to Clinical Implications. Int. J. Mol. Sci. 2024, 25, 4096. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25074096
Zhang S, Zhang Q, Lu Y, Chen J, Liu J, Li Z, Xie Z. Roles of Integrin in Cardiovascular Diseases: From Basic Research to Clinical Implications. International Journal of Molecular Sciences. 2024; 25(7):4096. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25074096
Chicago/Turabian StyleZhang, Shuo, Qingfang Zhang, Yutong Lu, Jianrui Chen, Jinkai Liu, Zhuohan Li, and Zhenzhen Xie. 2024. "Roles of Integrin in Cardiovascular Diseases: From Basic Research to Clinical Implications" International Journal of Molecular Sciences 25, no. 7: 4096. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25074096