Roles of Integrin in Cardiovascular Diseases: From Basic Research to Clinical Implications

Abstract

Cardiovascular diseases (CVDs) pose a significant global health threat due to their complex pathogenesis and high incidence, imposing a substantial burden on global healthcare systems. Integrins, a group of heterodimers consisting of α and β subunits that are located on the cell membrane, have emerged as key players in mediating the occurrence and progression of CVDs by regulating the physiological activities of endothelial cells, vascular smooth muscle cells, platelets, fibroblasts, cardiomyocytes, and various immune cells. The crucial role of integrins in the progression of CVDs has valuable implications for targeted therapies. In this context, the development and application of various integrin antibodies and antagonists have been explored for antiplatelet therapy and anti-inflammatory-mediated tissue damage. Additionally, the rise of nanomedicine has enhanced the specificity and bioavailability of precision therapy targeting integrins. Nevertheless, the complexity of the pathogenesis of CVDs presents tremendous challenges for monoclonal targeted treatment. This paper reviews the mechanisms of integrins in the development of atherosclerosis, cardiac fibrosis, hypertension, and arrhythmias, which may pave the way for future innovations in the diagnosis and treatment of CVDs.

Keywords: cardiac fibroblasts; cardiomyocytes; cardiovascular diseases; integrin antagonists and antibodies; integrins; nanotherapy; platelets; vascular endothelial cells; vascular smooth muscle cells.

Figure 1

The structure and classification of integrins. (A) The domain organization of integrins within primary structures. (B) The spatial arrangement of domains within the representative three-dimensional crystal structure of integrins. (C) Integrins include 24 types. They can be classified into 4 categories based on their receptor specificity: RGD receptors, laminin receptors, leukocyte-specific receptors, and collagen receptors. The same color in (A,B) indicating integrin structure corresponds to the same domain. Among them, the hvb and hyb domains in (A) correspond to the H domain in (B).

Figure 2

A summary diagram of the effects of integrins in six specific cell types that are mainly involved in the pathogenesis of cardiovascular diseases, including vascular endothelial cells (VECs), vascular smooth muscle cells (VSMCs), immune cells, platelets, cardiac fibroblasts, and cardiomyocytes. (A) The effects of integrins in VECs involved in the pathogenesis of atherosclerosis (AS) and hypertension. The extracellular matrix (ECM)–integrin interactions mediate VEC activation, dysfunction, and oxidation, thereby inducing vascular endothelial inflammation. (B) The pathogenic roles of integrins on VSMCs in AS. The binding of integrins to ligands in ECM can activate the characteristics of VSMCs, including VSMC migration, proliferation, differentiation, and calcification, which eventually leads to vascular stiffness. (C) The effects of integrins on immune cells involved in the pathogenic process of AS. The integrins on immune cells can activate several specific signaling pathways, such as PI3K/Akt and Syk/Src, which can induce cascade reactions and further activate the characteristics of immune cells, including migration, proliferation, adhesion, and phagocytosis, thereby causing thrombus formation. (D) The specific roles of integrins in platelet in AS pathogenesis. ECM–integrin interactions mainly participate in platelet activation, migration, and secretion, which subsequently causes blood coagulation, thrombosis, and AS plaque instability. (E) The effects of integrins on cardiac fibroblasts involved in cardiac fibrosis. The binding of integrins to ECM induces fibroblast activation, migration, and trans-differentiation, which promotes collagen synthesis and deposition. (F) The pathogenic roles of integrins on cardiomyocytes in arrhythmias. The activation of cardiomyocytes induced by ECM–integrin interactions mediates myocardial damage and myocardial electrical signal dysfunction, leading to cytoskeletal remodeling. Abbreviations: ECM: extracellular matrix, Rho: Ras homolog family, JNK: C-Jun NH2-terminal kinase, Src: serum creatinine, NF-kB: nuclear factor-k-gene binding, ANXA2: annexin A2, PIP1B: Arabidopsis thaliana aquaporin gene AthH2, FAK: focal adhesion kinase, ICAM-1: intercellular cell adhesion molecule-1, VCAM-1: vascular cell adhesion molecule-1, MMP2: matrix metalloproteinase2, TGF-β1: transforming growth factor-β1, α-SMA: α-smooth muscle actin, ERK1/2: extracellular signal-regulated kinase 1/2, Akt: protein kinase B, OPG: osteoprotegerin, YAP: Yes-associated protein, TAZ: tafazzin, Pyk2: protein tyrosine kinase 2, Ube2n: ubiquitin-conjugating enzyme 2N, Mdm2: mouse double minute 2 homolog, ACE2: angiotensin-converting enzyme 2, Smad 2/3: mothers against decapentaplegic homolog 2/3, Nox4: NADPH oxidase 4, PI3K: phosphoinositide 3-kinase, AMPK: AMP-activated protein kinase, PDIA1-Cit: protein disulfide isomerase A1-citrulline, PDIA1-Arg: protein disulfide isomerase A1-arginine, PAD4: peptidylarginine deiminase 4, CXCL1: chemokine (C-X-C motif) ligand 1, Gα13: guanine nucleotide-binding protein G(13) subunit alpha, mTOR: mammalian target of rapamycin, Vav3: Vav guanine nucleotide exchange factor 3, RhoGAP: Rho GTPase-activating protein, Rac-GEFs: Rac guanine nucleotide exchange factors, c-Src: cellular serum creatinine, PP2A: protein phosphatase 2A, PTEN: phosphatase and tensin homolog, ZO-1: Zona occludens protein 1, Vcl: vinculin, ILK: integrin-linked kinase, Cx43: connexin 43, PyR2: ryanodine receptor 2.

Figure 3

A summary diagram of integrin-based cardiovascular disease treatment methods and therapeutic drugs. (A) The use of integrin antagonists to block the binding of integrins with ligands, thereby inhibiting signal pathway transmission and CVD progression. (B) The use of NPs to enhance targeting specificity and bioavailability, delay drug release, and mitigate drug toxicity in the treatment of CVDs. Abbreviations: CVD: cardiovascular disease, VEC: vascular endothelial cell, VSMC: vascular smooth muscle cell, VEGF: vascular endothelial growth factor, NP: nanoparticle, RGD-peptide: arginine–glycine–aspartate peptide, RAP: rapamycin, cRGDfK peptide: cyclic arginyl–glycyl–aspartic acid–phenylalanine–lysine peptide, PLGA-Pep-PEG: poly (lactic-co-glycolic acid)–peptide–polyethylene glycol, RGDfC: Arg-Gly-Asp-Phe-Cys, RAP@T/R NPs: RAP targeted and responsive nanoparticles.