Proinflammatory cytokines and ageing of the cardiovascular-renal system
Introduction
Cardiovascular (CV) health deteriorates with age, and age is one of the strongest risk factors for cardiovascular complications, including myocardial infarction, stroke, heart failure, cardiac arrhythmias, and death related to cardiac diseases (Dhingra and Vasan, 2012). One of the hallmarks of ageing is a gradual increase in the concentration of circulating proinflammatory cytokines (PICs) throughout the human lifespan (Michaud et al., 2013). It is hypothesized that this chronic pro-inflammatory state in the elderly is either due to a delayed termination of the immune response or the result of cardiovascular damage accumulated over a lifetime (Baylis et al., 2013). Incremental increases in PIC levels may serve as a biomarker of chronic low-grade inflammatory processes and dysfunction of the immune system. However, in this review we argue that PICs are not just bystanders or biomarkers of underlying low-grade inflammation and CV diseases (CVDs), but rather that they serve as an important pathophysiological link between ageing, CV health, CV morbidity, and mortality. Furthermore, the development of different CVDs is often causally interconnected and one disease may eventually lead to the advancement of another. For example, growth of atherosclerotic plaques may result in ischemic heart disease and myocardial infarction, which in turn may lead to heart failure and cardiac arrhythmia. The development of both atherosclerosis and heart failure may be further enhanced by high blood pressure. In this light, chronic low-grade inflammation and increased concentration of PICs may serve as a common process underlying the pathomechanisms leading to the development and complications of CVDs. Thus, in this review we discuss how age-related increases in the levels of PICs promote: 1) autonomic imbalance and sympathoexcitation; 2) electrical instability of the myocardium and deterioration in cardiac function; 3) progression of atherosclerosis and vasoconstriction; 4) decline in renal function. By activation of these processes, PICs contribute to accelerated ageing of the CV system and increased susceptibility to CV morbidity and death (Fig. 1).
Section snippets
Age and cardiovascular morbidity and mortality
Cardiovascular diseases (CVDs), including: coronary heart disease, hypertension, heart failure, cardiac arrhythmias, and stroke, remain a leading cause of death worldwide. According to the Global Burden of Disease Study, in 2015 CVDs accounted for over 17.9 million deaths in all age groups globally and exceed the combined all age mortality of cancer (8.8 million), chronic respiratory diseases (3.8 million), Alzheimer’s disease (1.9 million), and diabetes mellitus (1.5 million) – the next four
Proinflammatory cytokines and ageing
A growing body of evidence points to the role of the immune system in both healthy and pathological ageing (Figueira et al., 2016; Michaud et al., 2013). The low-grade inflammatory state associated with ageing is coined “inflammageing,” and it is characterized by increased levels of circulating PICs, such as IL-1, IL-6, and TNF, as well as by infiltration of tissues by immune cells (Michaud et al., 2013). Emerging concepts suggest that inflammageing is driven by two overlapping processes –
PICs and autonomic nervous system
Sympathoexcitation has been linked to CVDs including hypertension, heart failure, and cardiac arrhythmias. Sympathetic activity to the cardiovascular system increases with age, which is manifested by elevated plasma catecholamine concentrations, increased cardiac and renal spillover of norepinephrine, and increased activity of the sympathetic nerves supplying the vessels of skeletal muscle in healthy humans (Seals and Esler, 2000; Shantsila et al., 2015).
Several lines of evidence point to a
Conclusions
A growing body of evidence strongly suggests that ageing of the cardiovascular system, which eventually leads to cardiovascular events, including myocardial infarction, stroke, heart failure, cardiac arrhythmias, and death, is at least in part attributable to the increased expression of proinflammatory cytokines. Thus, PICs are not only markers of chronic inflammation, but they also play an important role in triggering and augmenting undesirable changes, such as sympathoexcitation,
Conflict of interest
The authors declare no conflict of interest.
Author contributions
PS – wrote initial version of manuscript, reviewed draft of manuscript, prepared graphics; AS – wrote initial version of manuscript, reviewed draft of manuscript; MK – wrote initial version of manuscript, proofread final draft of manuscript; TZ - conceived idea of the review, drafted initial version of manuscript, provided inputs to all sections, revised, edited and approved the final version of manuscript.
Acknowledgments
The study was carried out with the use of CePT infrastructure financed by the European Union – the European Regional Development Fund within the Operational Programme “Innovative economy” for 2007–2013.
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2020, Biochemical PharmacologyCitation Excerpt :Cysteinyl leukotrienes (CysLTs) have been hypothesized to play a crucial role in the pathogenesis of atherosclerosis, as suggested by encouraging results obtained with montelukast, a CysLT1 receptor antagonists, as a cardiovascular protective drug in animal models and in still limited human clinical trials [19–21] and, limited to animal study, also on cerebrovascular diseases [22]. Several large-scale prospective cohort studies have also strongly suggested a role of cytokines in atherogenesis and cardiovascular diseases [23,24], and this was also corroborated by data obtained in animal studies [18]. A comprehensive review of these studies indicated that only for a few cytokines there are consistent data to classify them as typically pro-atherogenic (i.e. IL-1, IFN-γ, TNF-α, and M-CSF) or anti-atherogenic (IL-10), and that some cytokines (IL-4, IL-6 and GM-CSF) can exert pro- or anti-atherogenic effects depending on the experimental conditions [18].
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2019, Autonomic Neuroscience: Basic and ClinicalCitation Excerpt :In line with the above findings, it has been recently shown that high salt diet in the stroke-prone spontaneously hypertensive rats activates microglia of the PVN (Nakagawa et al., 2013). A number of studies showed that PICs acting in the brain promote shift towards pro-hypertensive regulation of the cardiovascular system (Smykiewicz et al., 2018; Shi et al., 2010; Segiet et al., 2019; Haspula and Clark, 2018). Infusions of TNF or IL-1β into the carotid artery, cerebral ventricles or directly into the brain centres involved in the cardiovascular control, such as PVN or SFO, increase arterial blood pressure (Segiet et al., 2019; Ufnal et al., 2006; Zera et al., 2008; Lu et al., 2009; Wei et al., 2015; Zera et al., 2016; Wei et al., 2013).
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2019, Journal of Molecular and Cellular CardiologyCitation Excerpt :Patel et al. reported that genes associated with an inflammatory response are expressed in the LV from adult patients with dilated cardiomyopathy, but not in left ventricles from pediatric patients with dilated cardiomyopathy [7]. Given the growing body of evidence that aging plays an important role in function and profile of the immune system, it is highly likely that pediatric patients have a unique inflammatory profile in HF when compared to adults [53,54]. One interesting study focused on the immune-response profile in mesenchymal stem cells isolated from rats of different ages.