Table 1.
Smoking and various types of cell function changes, phenotypic transitions and their molecular mechanisms.
| Cell type/plasma | Cigarette ingredients | Function changes/phenotypic transitions | Molecular mechanism | Disease | References |
|---|---|---|---|---|---|
| ECs | CSE | Dysfunction | Inhibit the transportation of HuR from the nucleus to the cytoplasm, and reduce the synthesis of GTPCH, thereby reducing the synthesis of BH4, to ultimately reduce the activity of eNOS and the production of NO | ASO | (38–40) |
| CSE | Dysfunction | Reduce the expression of DHFR, inhibit the synthesis of BH4, and then reduce the activity of eNOS. | ASO | (41) | |
| CSE | Dysfunction | Promote the increase of thiocyanate (SCN-) expression, thereby promoting the increase of HOSCN synthesis and reducing the activity of eNOS and the production of NO | ASO | (42–44) | |
| CSE | Dysfunction | Reactive oxygen/nitrogen interacts with VEGFR2, leading to post-translational modification, thereby inhibiting the downstream Akt/eNOS/NO signaling pathway | ASO | (45) | |
| CSE | Dysfunction | Decrease the expression of SIRT3 and increase the over-acetylation of SOD, which leads to the obstruction of O2 clearance and excessive accumulation | ASO | (51, 52) | |
| CSE | Dysfunction | Activate NADPH oxidase and increase the production of endothelial O2−. The increased O2− will consume tetrahydrobiopterin, a cofactor required by eNOS | ASO | (39, 53) | |
| CSE | Dysfunction | Downregulate SIRT1, promote the increase of eNOS acetylation, thereby reducing the production of NO | ASO | (54) | |
| CSE | Dysfunction | The production of ROS will lead to the rapid inactivation of NO and the formation of peroxynitrite : Reducing the biological activity of NO; Separating BH4 and destroying the stability of eNOS; Promoting the modification of protein (eNOS) and changing the metabolic pathway | ASO | (23, 55–59) | |
| CSE | Dysfunction | Inhibit the uptake of arginine and reduce the expression of arginine transporter CAT1, thereby reducing the synthesis of NO | ASO | (74) | |
| CSE | Dysfunction | Misfolded proteins reduce protein (eNOS) synthesis. At the same time, the interaction of unfolded proteins leads to phosphorylation of PERK and eIF2a, prolonging endoplasmic reticulum stress and activates autophagy | ASO | (76) | |
| CSE | Dysfunction | Activate NF-kB and NLRP3 signaling pathways to promote mitochondrial damage, leading to energy disorders | ASO | (56, 62, 63, 77) | |
| CSE | Dysfunction | Upregulate the expression of galectin-3, thereby promoting the upregulation of p-AMPK and down-regulation of p-mTOR, leading to increased autophagy expression | ASO | (78) | |
| CSE | Dysfunction | Activate Rho kinase and promote phosphorylation of eNOS (Thr113), thereby inhibiting the production of NO in ECs | ASO | (66, 67) | |
| CSE | Dysfunction | Increased expression of ETB receptors causes endothelial dysfunction through the action of ET-1 | ASO | (121, 124) | |
| CSE | Arterial-spasm thrombosis | Interact with eNOS mutated gene locus to reduce the production of vasodilatory NO | TAO | (128) | |
| Monocyte-macrophages | CSE | Inflammation | Produce various chemokines and pro-inflammatory cytokines (CCR2, MCP-1, MCP-3), thereby increasing the adhesion of monocytes to the blood vessel wall | ASO | (81–83) |
| CSE | Inflammation | Activation of PKC leads to increased expression of CD11b and VCAM1, ICAM-1 and ELAM-1, thereby increasing the adhesion of monocytes to the vessel wall | ASO | (84, 85) | |
| PAH | Affect gene transcription and expression | Activate the AHR signaling pathway and drive the methylation of the AHRR gene to change the DNA conformation and affect the interaction between protein factors and DNA | ASO | (93–95) | |
| CSE | Cell transformation | Activate the RANKL-RANK pathway to promote the transformation of macrophages into osteoclasts | AAA | (129) | |
| CSE | Extracellular matrix degradation | Upregulate NFATc1, promote macrophage activation, and promote the expression of osteoclast production related proteases TRAP, cathepsin K and MMP-9 | AAA | (130, 131) | |
| CSE | Osteoclastogenesis | Activate macrophages through NF-kB, increasing the expression of MCP-1, MMP-9, IL-8 and TNF-α | AAA | (132, 133) | |
| CSE | Tissue remodeling and inflammation | Increased expression of MMP-9 and MMP-2: Activating TGF-β; Inactivating protein-1α by cleaving serpins at an inhibitory site region, which will induce the expression of proinflammatory molecules | AAA | (134, 135) | |
| VSMCs | CSE | Contraction | Activate Rho kinase and regulate the sensitivity of calcium ions | ASO | (68, 69) |
| Nicotine | Phenotypic transitions | Activate nAChRs and GPCRs to promote the conversion of contractile type to synthetic type | ASO | (105) | |
| Nicotine | Cytoskeleton remodelingMatrix degradationCell Proliferation | Increase calcium influx: Changing calpain-1 conformation, then activating PKC to promote actin morphology changes; Activating MMP-2/MMP-9 signaling pathway; Activating ERK1/2-Egr−1 signal pathway | ASO | (106–109) | |
| Nicotine | Proliferation and migration | Promote the phosphorylation of STAT3, Akt, and mTOR through the AChRα1 receptor | ASO | (110) | |
| Nicotine | Proliferation and migration | Activate the EGFR-ERK pathway and promote the release of VEGF | ASO | (111) | |
| Nicotine | Phenotypic transitions | Cause oxidative stress, which activates the NF-kB signaling pathway, promotes autophagy and the transition of VSMCs from contractile to synthetic | ASO | (112, 113) | |
| CSE | Contraction | Activate MEK1/2, ERK1/2, MAPK, NF-kB, thereby promoting the upregulation of ETA receptor expression | ASO | (118–123) | |
| CSE/ Nicotine | Proliferation | Promote the production of bFGF, which in turn activates the p-ERK-p-c-Jun-cyclinD1 pathway | ASO | (125, 126) | |
| CSE | Contraction | Reduce the production of NO and PGI2 in ECs, thereby promoting hyperpolarization of VSMCs | ASO | (127) | |
| Plasma | CSE | Inflammation | Increase expression of MMP-9 and HMGB-1 | TAO | (136, 137) |
CSE, Cigarette smoke extract; VSMCs, Vascular smooth muscle cells; ECs, Endothelial cells; DHFR, Dihydrofolate reductase; PAH, Polycyclic aromatic hydrocarbons; GTPCH, GTP cyclohydrolase; eNOS, Endothelial nitric oxide synthase; NO, Nitric oxide; ROS, Reactive oxygen species; VEGF, Vascular endothelial growth factor; VEGFR2, Vascular Endothelial Growth Factor Receptor 2; BH4, Tetrahydrobiopterin; PKC, Protein kinase C; TGF-β,Transforming growth factor-β; MMP, Matrix metalloproteinase; nAChRs, Nicotinic acetylcholine receptors; GPCRs, G protein-coupled receptors; HMGB1, High mobility group box 1; AHR, Aryl hydrocarbon receptor; CCR2, Chemokine receptor 2; MCP-1, Monocyte chemotactic protein 1; MCP-3, Monocyte chemotactic protein 3; TNF-α, Tumor necrosis factor-α; ASO, Atherosclerosis; TAO, Thromboangiitis obliterans; AAA, Abdominal aortic aneurysm.