New frontiers in the treatment of comorbid cardiovascular disease in chronic obstructive pulmonary disease

Abstract

Chronic obstructive pulmonary disease (COPD) is a disease characterised by persistent airflow limitation that is not fully reversible and is currently the fourth leading cause of death globally. It is now well established that cardiovascular-related comorbidities contribute to morbidity and mortality in COPD, with approximately 50% of deaths in COPD patients attributed to a cardiovascular event (e.g. myocardial infarction). Cardiovascular disease (CVD) and COPD share various risk factors including hypertension, sedentarism, smoking and poor diet but the underlying mechanisms have not been fully established. However, there is emerging and compelling experimental and clinical evidence to show that increased oxidative stress causes pulmonary inflammation and that the spill over of pro-inflammatory mediators from the lungs into the systemic circulation drives a persistent systemic inflammatory response that alters blood vessel structure, through vascular remodelling and arterial stiffness resulting in atherosclerosis. In addition, regulation of endothelial-derived vasoactive substances (e.g. nitric oxide (NO)), which control blood vessel tone are altered by oxidative damage of vascular endothelial cells, thus promoting vascular dysfunction, a key driver of CVD. In this review, the detrimental role of oxidative stress in COPD and comorbid CVD are discussed and we propose that targeting oxidant-dependent mechanisms represents a novel strategy in the treatment of COPD-associated CVD.

Keywords: cardiovascular disease; chronic obstructive pulmonary disease; cigarette smoke; lung inflammation; oxidative stress; vascular dysfunction.

Figure 1

Formation of ROS and RNS in response to CS CS exposure activates immune cells, which generate superoxide radical (O₂^•−), through activation of NOX-2, which either reacts with NO to form harmful peroxynitrite (ONOO⁻) or be converted into harmful hydrogen peroxide (H₂O₂) under the influence of SOD, which in the presence of ferrous iron (Fe²⁺) is converted into hydroxyl radicals (•OH) via the Fenton reaction. Both GPx and CAT convert H₂O₂ into H₂O and O₂, reducing circulating ROS. Abbreviation: RNS, reactive nitrogen species.

Figure 2

Schematic of lung inflammation and pathogenesis of COPD and comorbid CVD Exposure to CS and air pollution activates immune cells (e.g. macrophages, neutrophils) which drives ROS production and systemic inflammation which promote CVD onset and progression ultimately leading to CVD-associated death.

Figure 3

Blood vessel homoeostasis The role of NO synthase (NOS) and l-arginine metabolism in endothelial-dependent blood vessel dilation (A) under normal conditions and (B) in an oxidative environment such as that seen in COPD. NO-dependent vasodilators or an increase in localised blood flow stimulate the release of intracellular calcium through receptor (R) binding or an increase in shear flow, respectively. This in turn up-regulates the activity of constitutive NO synthase (cNOS), causing the catalytic conversion of the amino acid l-arginine into NO. NO then diffuses from the superficial endothelial cell layer to the underlying smooth muscle. In smooth muscle cells, guanylyl cyclase (GC) activity is induced by an increase in NO, causing this enzyme to convert guanosine triphosphate (GTP) into cyclic guanosine monophosphate (cGMP) and thus resulting in a vasodilatory response. In an oxidative environment (i.e. smokers with COPD) there is an overall reduction in the bioavailability of l-arginine because of overexuberant ROS production and therefore reduced NO expression and impaired vasodilation.

Figure 4

Intrinsic and extrinsic coagulation pathways, platelet activation, adhesion and aggregation, in both healthy and diseased states Activation of both the intrinsic and extrinsic coagulation pathways drives prothrombin activation, in turn up-regulating thrombin-dependent conversion of fibrinogen into fibrin, promoting platelet activation. This platelet activation causes platelet plug formation and a localised inflammatory response under normal pathological conditions, which cause collagen deposition and wound repair. In a diseased state like that seen in COPD, this process becomes dysregulated, driving platelet hyperactivation, exaggerated inflammatory responses, collagen deposition and immune cell activation, all of which are contributing factors of atherosclerotic lesion formation, vascular dysfunction and plaque instability that can ultimately lead to myocardial infarction, cerebral artery occlusion (stroke) and death.