Diabetes and ageing-induced vascular inflammation

Abstract

Diabetes and the ageing process independently increase the risk for cardiovascular disease (CVD). Since incidence of diabetes increases as people get older, the diabetic older adults represent the largest population of diabetic subjects. This group of patients would potentially be threatened by the development of CVD related to both ageing and diabetes. The relationship between CVD, ageing and diabetes is explained by the negative impact of these conditions on vascular function. Functional and clinical evidence supports the role of vascular inflammation induced by the ageing process and by diabetes in vascular impairment and CVD. Inflammatory mechanisms in both aged and diabetic vasculature include pro-inflammatory cytokines, vascular hyperactivation of nuclear factor-кB, increased expression of cyclooxygenase and inducible nitric oxide synthase, imbalanced expression of pro/anti-inflammatory microRNAs, and dysfunctional stress-response systems (sirtuins, Nrf2). In contrast, there are scarce data regarding the interaction of these mechanisms when ageing and diabetes co-exist and its impact on vascular function. Older diabetic animals and humans display higher vascular impairment and CVD risk than those either aged or diabetic, suggesting that chronic low-grade inflammation in ageing creates a vascular environment favouring the mechanisms of vascular damage driven by diabetes. Further research is needed to determine the specific inflammatory mechanisms responsible for exacerbated vascular impairment in older diabetic subjects in order to design effective therapeutic interventions to minimize the impact of vascular inflammation. This would help to prevent or delay CVD and the specific clinical manifestations (cognitive decline, frailty and disability) promoted by diabetes-induced vascular impairment in the elderly.

Figure 1. Ageing‐ or diabetes‐induced inflammatory mechanisms cause vascular dysfunction increasing cardiovascular risk

Ageing or diabetes is associated with a disruption in the endothelial environment due to the presence of high levels of both reactive oxygen species (for example, superoxide (O₂.⁻) and hydrogen peroxide (H₂O₂)), and pro‐inflammatory mediators produced locally or systemically. A pro‐oxidative stress scenario impacts negatively on endothelial function by quenching nitric oxide (NO) and therefore reducing its availability. Circulating pro‐inflammatory cytokines (for examples TNF‐α) also contribute to endothelial malfunction through direct induction of iNOS or through the activation of a redox‐sensitive pro‐inflammatory nuclear factor κB (NF‐κB), which in turn activates different enzymes (iNOS, COX‐2) leading to peroxynitirite (ONOO⁻) formation and increased production of contractile factors. A regulation of COX‐1 is also observed in ageing. A close interaction between oxidative stress and chronic low‐grade inflammation develops in the microenvironment of aged or diabetic arteries, exacerbating one another and creating a vicious cycle. This translates into an endothelial phenotype characterized by the presence of endothelial dysfunction that consequently makes aged or diabetic individuals prone to develop cardiovascular disease. COX, cyclooxygenase; CRP, C reactive protein; IL‐6, interleukin‐6; IL‐1β, interleukin‐1β; iNOS, inducible nitric oxide synthase; PGH2, prostaglandin H2; TNF‐α, tumor necrosis factor‐α; TXA2, thromboxane A2.

Figure 2. Exaggerated vascular dysfunction when ageing and diabetes co‐exist: role of basal low‐grade inflammation

In young arteries (upper left), the development of diabetes induces oxidative stress and inflammation that is counteracted by an anti‐inflammatory/stressor response by modulatory systems (Nrf2, sirtuins, etc.) that mitigates in some degree the impact of diabetes on NO availability and vascular function (upper right). In aged arteries, there exists a low‐grade inflammation that moderately impacts vascular function and NO availability (lower left). In this situation, the development of diabetes induces further oxidative stress and inflammation, but the basal oxidant and inflammatory conditions prevent a balanced response by defective modulatory systems resulting in exacerbated NO deficit and vascular dysfunction (lower right). A similar situation could result when a diabetic condition persists and the ageing process further impairs vascular function. COX, cyclooxygenase; IL‐6, interleukin‐6; iNOS, inducible nitric oxide synthase; NF‐κB, nuclear factor‐κB; ROS, reactive oxygen species; TNF‐α, tumour necrosis factor‐α.

Figure 3. Ageing‐induced modification of the vascular inflammatory insult driven by diabetes

Exemplification of two possible interactions between vascular ageing and diabetes. A, the vascular damage resulting from glycated haemoglobin (HbG) increase is associated with diabetic conditions (diabetes mellitus (DM)/hyperglycaemia) in young and aged vessels. In young vessels (left), superoxide anion (SO⁻) generated by HbG induces NF‐κB expression and its downstream inflammatory mediators such as cyclooxygenase (COX) and inducible nitric oxide synthase (iNOS). This inflammatory response is translated into vascular damage through mechanisms involving, for example, peroxinitrite (ONOO⁻) formation. In contrast, aged vessels (right) manifest chronic low‐grade inflammation with up‐regulation of NF‐кB and inflammatory mediators as well as increased SO⁻ generation that results in ageing‐induced vascular damage. Under these conditions, diabetic insult leading to SO⁻ generation by HbG does not further induce vascular inflammatory response and no appreciable additional vascular damage. B, by contrast, there is a lack of vascular damage due to diabetes‐induced high glucose concentrations in the absence of inflammatory conditions in young vessels (left), while the chronic low‐grade inflammation caused by ageing in the vasculature (right) amplifies the deleterious effects driven by hyperglycaemia, which results in an exacerbated vascular damage, greater than that caused by normoglycaemic ageing. Alterations driven by ageing are highlighted in blue. Epidemiological and functional evidence in older diabetic animals and humans suggest that the interaction exemplified in B predominates over that in A.