Cigarette Smoking and Atherosclerotic Cardiovascular Disease

Abstract

The detrimental effects of cigarette smoking on cardiovascular health, particularly atherosclerosis and thrombosis, are well established, and more detailed mechanisms continue to emerge. As the fundamental pathophysiology of the adverse effects of smoking, endothelial dysfunction, inflammation, and thrombosis are considered to be particularly important. Cigarette smoke induces endothelial dysfunction, leading to impaired vascular dilation and hemostasis regulation. Factors contributing to endothelial dysfunction include reduced bioavailability of nitric oxide, increased levels of superoxide anion, and endothelin release. Chronic inflammation of the vascular wall is a central pathogenesis of smoking-induced atherosclerosis. Smoking systemically elevates inflammatory markers and induces the expression of adhesion molecules and cytokines in various tissues. Pattern recognition receptors and damage-associated molecular patterns play crucial roles in the mechanism underlying smoking-induced inflammation. Smoking-induced DNA damage and activation of innate immunity, such as the NLRP3 inflammasome, cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, and Toll-like receptor 9, are shown to amplify inflammatory cytokine expression. Cigarette smoke-induced oxidative stress and inflammation influence platelet adhesion, aggregation, and coagulation via adhesion molecule upregulation. Furthermore, it affects the coagulation cascade and fibrinolysis balance, causing thrombus formation. Matrix metalloproteinases contribute to plaque vulnerability and atherothrombotic events. The impact of smoking on inflammatory cells and adhesion molecules further intensifies the risk of atherothrombosis. Collectively, exposure to cigarette smoke exerts profound effects on endothelial function, inflammation, and thrombosis, contributing to the development and progression of atherosclerosis and atherothrombotic cardiovascular diseases. Understanding these intricate mechanisms highlights the urgent need for smoking cessation to protect cardiovascular health. This comprehensive review investigates the multifaceted mechanisms through which smoking contributes to these life-threatening conditions.

Keywords: Atherothrombosis; DAMPs; Endothelial dysfunction; Inflammation; Smoking.

Fig.1. Cigarette smoke-induced endothelial dysfunction

Free radicals and peroxynitrite anion (ONOO^-) from the vapor phase of cigarette smoke or produced via redox cycles activate ECs by inducing endothelial selectins (P- and E-selectin), ICAM-1, VCAM-1, and platelets. Monocyte adhesion and transendothelial migration are induced by increased adhesion molecule expression. Endothelial activation is characterized by reduced NO availability and results in the loss of function of vascular smooth muscle cells. Smoking-induced endothelial dysfunction is associated with increased ET-1 release. Smoke extract disrupts mitochondrial function and can trigger inflammation via damage-associated molecular patterns. Inflammatory and proatherogenic cytokines released from EC in response to smoke exposure further lead to endothelial dysfunction (refer to the section on inflammation). EC, endothelial cells; VSMC, vascular smooth muscle cells; ICAM-1, intercellular adhesion molecule-1; VCAM-1, vascular cell adhesion molecule-1; NO, nitric oxide; ET-1, endothelin 1. Created using Biorender.com.

Fig.2. Schematic diagram of the mechanisms of inflammation induced by smoking

The pathogenesis of atherosclerosis is mainly driven by chronic inflammation in the vascular wall, with cigarette smoking as an inflammatory trigger. The innate immune system, involving pattern recognition receptors, plays a pivotal role, particularly TLR9, NLRP3/AIM2 inflammasome, and cGAS-STING, in atherosclerotic lesions. Cigarette smoke-induced cGAS is mainly activated by cytosolic-free mtDNA released through minority MOMP. Both the TLR9 and cGAS pathways lead to an increased expression of inflammatory cytokines, such as IL-6 and IL-8. Cytosolic-free mtDNA also activates DNA-sensing AIM2 inflammasome, and cigarette smoke-induced ROS activates NLRP3 inflammasome; both induce GSDMD-mediated pyroptosis and release of proinflammatory cytokines such as IL-1β and IL-18 into the extracellular space. In addition, cigarette smoke triggers another form of cell death, ferroptosis, leading to the activation of redox-sensitive transcription factor, MMP expression, and inflammation in VSMC. Damaged tissues release DAMPs, contributing to innate immunity and inflammation. Other mechanisms such as NETs generate ROS and DAMPs and activates NLRP3 inflammasome in macrophages; they also contribute to atherogenesis. The cell-specific mechanisms of inflammation induced by smoking is presented in this figure. EC, endothelial cell; VSMC, vascular smooth muscle cell; TLR, Toll-like receptor; cGAS, cyclic GMP–AMP synthase; STING, stimulator of interferon genes; mtDNA, mitochondrial DNA; MOMP, mitochondrial outer membrane permeability; IL, interleukin; ROS, reactive oxygen species; GSDMD, gasdermin D; MMP, matrix metalloprotease; DAMPs, damage-associated molecular patterns; NETs: neutrophil extracellular traps. Created using Biorender.com.

Fig.3. Cigarette smoke-induced atherothrombosis

Cigarette smoke activates endothelial cells, which enhances the expression of endothelial selectins (P- and E-selectin), ICAM-1, and VCAM-1, promoting the adhesion of monocytes/lymphocytes and platelets to inflammatory endothelium. Expression of vWF expressed in the exposed subendothelial tissue from injured dysfunctional endothelial cells promotes platelet adhesion and aggregation reactions, leading to platelet thrombus formation. Moreover, smoking contributes to the formation of vulnerable plaques through increased inflammation and upregulated activity of MMPs. Exposure to cigarette smoke induces the expression of MMP-9 and MMP-12 in macrophage, MMP-1, MMP-8, and MMP-9 in the endothelial cells, and MMP-2 and MMP-9 in VSMC. ICAM, intercellular adhesion molecule; VCAM, vascular cell adhesion molecule; vWF, von Willebrand factor; MMP, matrix metalloprotease; VSMC, vascular smooth muscle cells. Created using Biorender.com.