Current Vascular Pharmacology - Volume 20, Issue 3, 2022

Endothelial dysfunction is a crucial physiopathological mechanism for cardiovascular diseases that results from the harmful impact of metabolic disorders. Irisin, a recently discovered adipomyokine, has been shown to exert beneficial metabolic effects by increasing energy consumption, improving insulin sensitivity, and reducing the proinflammatory milieu. Multiple preclinical models have assessed irisin's possible role in the development of endothelial dysfunction, displaying that treatment with exogenous irisin can decrease the production of oxidative stress mediators by up-regulating Akt/mTOR/Nrf2 pathway, promote endothelial-dependent vasodilatation through the activation of AMPK-PI3K-AkteNOS pathway, and increase the endothelial cell viability by activation of ERK proliferation pathway and downregulation of Bad/Bax/Caspase 3 pro-apoptotic pathway. However, there is scarce evidence of these mechanisms in clinical studies, and available results are controversial. Some have shown negative correlations of irisin levels with the burden of coronary atherosclerosis and leukocyte adhesion molecules' expression. Others have demonstrated associations between irisin levels and increased atherosclerosis risk and higher carotid intima-media thickness. Since the role of irisin in endothelial damage remains unclear, in this review, we compare, contrast, and integrate the current knowledge from preclinical and clinical studies to elucidate the potential preventive role and the underlying mechanisms and pathways of irisin in endothelial dysfunction. This review also comprises original figures to illustrate these mechanisms.

Glycine Receptors (GlyRs) are cell-surface transmembrane proteins that belong to the Cysloop ligand-gated ion channels superfamily (Cys-loop LGICs). Functional glycine receptors are conformed only by α-subunits (homomeric channels) or by α- and β-subunits (heteromeric channels). The role of glycine as a cytoprotective is widely studied. New information about glycine modulation of vascular endothelial cells (ECs) function emerged last year. Glycine and its receptors are recognized to play a role as neurovascular protectors by a mechanism that involves α2GlyRs. Interestingly, the expression of α2GlyRs reduces after stroke injury. However, glycine reverses the inhibition of α2GlyRs by a mechanism involving the VEGF/pSTAT3 signaling. On the other hand, consistent evidence has demonstrated that ECs participate actively in the innate and adaptive immunological response. We recently reported that GlyRs are modulated by interleukin-1β, suggesting new perspectives to explain the immune modulation of vascular function in pathological conditions such as cerebrovascular stroke. In this work, we distinguish the role of glycine and the allosteric modulation of glycine receptors as a new therapeutic target to confront post-ischemic injury.

Interleukin-10 (IL-10) is an important immunomodulatory cytokine, initially characterized as an anti-inflammatory agent released by immune cells during infectious and inflammatory processes. IL-10 exhibits biological functions that extend to the regulation of different intracellular signaling pathways directly associated with vascular function. This cytokine plays a vital role in vascular tone regulation by changing important proteins involved in vasoconstriction and vasodilation. Numerous investigations covered here have shown that therapeutic strategies inducing IL-10 exert anti-inflammatory, anti-hypertrophic, anti-hyperplastic, anti-apoptotic and antihypertensive effects. This non-systematic review summarizes the modulating effects mediated by IL-10 in vascular tissue, particularly on vascular tone, and the intracellular pathway induced by this cytokine. We also highlight the advances in IL-10 manipulation as a therapeutic target in different cardiovascular pathophysiologies, including the physiological implications in animals and humans. Finally, the review illustrates current and potential future perspectives of the potential use of IL-10 in clinical trials based on the clinical evidence.

Cardiovascular diseases cause considerable health and economic burden, as they are the leading cause of disability and death in the western world. Inactivity, hypertension, obesity, diabetes, and smoking are among the classic risk factors for cardiovascular disease. From a pathophysiological point of view, the arteries of our body bear the harmful stimuli produced by these factors and respond to them with a series of intricate adaptive mechanisms. Vascular remodeling constitutes an adaptive response to hemodynamic and inflammatory alterations associated with hypertension, diabetes, and other illnesses. Thickening of the arterial walls leads to endothelial dysfunction and increases the risk of cerebrovascular and coronary events. During the last decades, antiplatelet, lipid-lowering, and antihypertensive therapies have been the cornerstone of primary and secondary prevention of cardiovascular events. However, it is still unknown whether their efficacy is strictly associated with the control of the classical risk factors or their additive effects on vascular inflammation. Since inflammation of arterial walls is related to the pathogenesis of atherosclerosis, it has been hypothesized that anti-inflammatory therapies could prevent and treat vascular remodeling. Clinical trials based on canakinumab or hydroxychloroquine provide further insight into the role of inflammation in the pathophysiology of cardiovascular diseases. In this review, we have analyzed evidence and suggested that inflammation may play an important role in the final pathway of many cardiovascular risk factors.

Western-style diet often leads to food overconsumption, which triggers the development of comorbidities, such as obesity, insulin resistance, hypercholesterolemia, hypertriglyceridemia, type 2 diabetes, and heart failure (HF). Several studies suggest that intermittent fasting (IF) protects against the development of those morbidities. This study presents evidence of the beneficial effects of IF on HF. Based on the current evidence, we discuss the potential molecular mechanisms by which IF works and where liver ketone bodies (KBs) play important roles. There is evidence that IF promotes a metabolic switch in highly metabolic organs, such as the heart, which increases the use of KBs during fasting. However, besides their role as energy substrates, KBs participate in the signaling pathways that control the expression of genes involved in oxidative stress protection and metabolism. Several molecular factors, such as adenosine monophosphate-activated protein kinase (AMPK), peroxisome proliferatoractivated receptor, fibroblast growth factor 21 (FGF21), sirtuins, and nuclear factor erythroid 2-related factor 2 (Nrf2) are involved. Furthermore, IF appears to maintain circadian rhythm, which is essential for highly metabolically active organs. Finally, we highlight the important research topics that need to be pursued to improve current knowledge and strengthen the potential of IF as a preventive and therapeutic approach to HF.

Sustained and intermittent hypoxia produce vasoconstriction, arterial remodeling, and hypertension in the lung. Stromal interaction molecule (STIM)-activated transient receptor potential channels (TRPC) and calcium release-activated calcium channel protein (ORAI) channels (STOC) play key roles in the progression of pulmonary hypertension in pre-clinical models of animals subjected to sustained and intermittent hypoxia. The available evidence supports the theory that oxidative stress and hypoxic inducible factors upregulate and activate STIM-activated TRPC-ORAI Ca²⁺ channels, contributing to the pulmonary remodeling and hypertension induced by sustained hypoxia. However, less is known about the effects of oxidative stress and hypoxic inducible factors on the modulation of STIM-activated TRPC-ORAI channels following chronic intermittent hypoxia. In this review, we examined the emerging evidence supporting the theory that oxidative stress and hypoxic inducible factors induced by intermittent hypoxia upregulate and activate STIM-activated TRPC-ORAI Ca²⁺ channels. In addition, we used bioinformatics tools to search public databases for the genes involved in the upregulation of STIMactivated TRPC-ORAI Ca²⁺ channels and compare the differential gene expression and biological processes induced by intermittent and sustained hypoxia in lung cells.

Diseases of the cardiovascular system have been the biggest cause of mortality for the majority of the last century, currently contributing to almost a third of deaths every year globally. Ageing associates with changes to the structure and function of the heart and vascular system that progressively increase the incidence of abnormalities, morbidity, and cardiovascular disease. The burden of ageing and its relationship to cardiovascular disease risk highlights the need for more research into the underlying mechanisms involved and how they may be treated and/or prevented. Factors influencing adrenergic dysfunction may explain a significant part of the age-related deterioration in health and responsiveness of the cardiovascular system. Increased sympathetic activity in old age overstimulates adrenergic receptors and causes detrimental changes within the associated signalling mechanisms, including a reduction in receptor number and downstream effector efficiency. Pharmacological agents, such as metformin, resveratrol, beta-blockers, and angiotensin converting enzyme (ACE) inhibitors, have been identified as potential anti-ageing therapies with cardiovascular effects, which may be beneficial in treating the decline in cardiovascular function with old age. Regular exercise has also shown promise in the prevention and treatment of harmful age-related effects on the cardiovascular system. This review will investigate age-associated vascular and cardiac remodelling, and the link between adrenergic dysfunction and vascular and cardiac control. This review will also consider whether pharmacological or non-pharmacological therapies are most effective, or indeed complimentary to potentially optimised ageing of the cardiovascular system and improved quality of life in the elderly.

Background: Testicular aches have been reported to occur on exposure to high altitude (HA). As a painful expression of venous congestion at the pampiniform plexus, varicocele (VC) might be a consequence of cardiovascular adjustments at HA. Chile’s National Social Security Regulatory Body (SUSESO) emphasized evaluating this condition in the running follow-up study “Health effects of exposure to chronic intermittent hypoxia in Chilean mining workers.” Objectives: This study aimed at investigating the prevalence of VC in a population usually shifting between sea level and HA, thereby intermittently being exposed to hypobaric hypoxia. Methodology: Miners (n=492) agreed to be examined at their working place by a physician, in the context of a general health survey, for the presence of palpable VC, either visible or not. Among them was a group exposed to low altitude (LA) <2,400 m; n=123; another one exposed to moderate high altitude (MHA) working 3,050 m; n=70, and a third one exposed to very high altitude (VHA) >3,900 m, n=165. The Chi² test and Kruskal-Wallis test were used for the descriptive analyses, and logistic regression was applied to evaluate the association of VC with exposure to HA. The Ethics Committee for Research in Human Beings, Faculty of Medicine, University of Chile, approved this project. Results: VC prevalence (grades 2 and 3) was found to be 10% at LA, 4.1% at MHA, and 16.7% at VHA (p≤0.05). Hemoglobin oxygen saturation (SaO2) was lower, and hemoglobin concentrations were higher in workers with high-grade VC at VHA compared to LA and MHA (Wilcoxon tests, p<0.001). Odds ratios (OR) for the association of VC with HA were 3.7 (95%CI: 1.26 to 12.3) and 4.06 (95%CI: 1.73 to 11.2) for MHA and VHA, respectively. Conclusion: Association of VC with HA, a clinically relevant finding, may be related to blood volume centralization mediated by hypobaric hypoxia.