Salivary lipid mediators: Key indexes of inflammation regulation in heart failure disease

Cardiovascular diseases (CVDs) represent a global burden whose incidence continues to increase [1]. CVDs refer to all the disorders involving the heart and blood vessels, such as coronary heart disease, peripheral vascular disease, and heart failure (HF) [1]. A non-healthy lifestyle, e.g. smoking, bad dietary habits, physical inactivity or chronic stress, are associated with the principal CVDs risk factors, including hypertension, hypercholesterolemia, obesity and diabetes [2]. Oxidative stress and inflammation have gained increasing attention as key pathophysiological factors in cardiovascular events [3], such as HF syndrome. HF is a leading cause of hospitalization and mortality in the West [4], as well as a key comorbidity in cognitive impairment in the elderly [5]. HF disease has been associated with poor quality of life, recurring hospitalizations, and a reduced survival rate [6,7]. The diagnosis of HF is established only after a clear appearance of the clinical symptoms, thus highlighting the importance of understanding and modulating its pathophysiological mechanisms for a successful patient management [8]. Dysfunction of cardiac mitochondria is a hallmark of HF and a leading cause of oxidative stress, which in turn causes myocardial tissue damage and inflammation thus contributing to heart failure progression [9]. Oxidative stress and inflammation are strictly related to each other, both in the acute phase of the disease, e.g., after myocardial infarction, and during chronic cardiac remodelling [9]. Antioxidants or anti-inflammatory drugs have thus been proposed as supporting therapies for subjects either at high risk or who suffer from established heart failure [9].

The immune-inflammatory response is regulated among cells by macrophages through the expression and secretion of various receptors and soluble molecules, such as cytokines, chemokines and lipid mediators [10]. Lipid mediators, also termed oxylipins, are generated both by omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) through enzymatic (e.g., prostanoids, epoxy, and hydroxy fatty acids) and non-enzymatic (e.g., isoprostanoids) oxidation reactions [11,12]. Oxylipins are implicated not only in the initial phases of inflammation, but also in the precise regulation of its course and resolution. At the very beginning of the inflammatory insult, M1-type macrophages induce the release of pro-inflammatory mediators, such as prostaglandins, thromboxanes, and leukotrienes, leading to the classic signs of inflammation [13]. The production of oxylipins then undergoes a lipid mediator class switching because of the shift from M1-to anti-inflammatory M2-type macrophages. M2-macrophages play a key role in producing pro-resolving mediators (SPMs), including lipoxins, resolvins, protectins and maresins [14], roughly 12 h after the beginning of the inflammatory response. SPMs lower the inflammatory response and even promote its resolution by decreasing the influx of neutrophils to tissues, enhancing non-phlogistic recruitment of monocytes into tissues, as well as decreasing the production of pro-inflammatory mediators [15]. The lack of control of the process and SPM deregulation can lead to a perpetuating inflammatory cycle [16], typical of chronic inflammation. This form of low-grade chronic inflammation often accompanies metabolic disorders, such as obesity and hypertension, and represents a fundamental player in the onset of CVDs [17]. During chronic inflammation, both pro-inflammatory and pro-resolving mediators are present, with specific molecules being over- or under-expressed, according to the different inflammatory diseases and tissues.

All this evidence suggests that several families of bioactive lipid mediators coexist which are differently expressed during the various stages of inflammation, and that these bioactive compounds are needed to work together to regulate the inflammatory response. To date, a fully detailed temporal characterization of these mediators during the different stages of inflammation is still lacking and represents a future challenge in the study of CVDs. In the present work we thus propose a powerful MS-based platform for the quantitation of sixty salivary oxylipins in CVD samples. Saliva, which represents a non-invasive and painless alternative to blood, was collected from patients suffering from acute and chronic heart failure, obesity and hypertension for a comprehensive lipid mediator profiling of one of the most studied CVDs and its main risk factors.

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