Current Pharmaceutical Design - Volume 26, Issue 30, 2020

Cardiovascular diseases (CVD) are considered a major health problem worldwide, being the main cause of mortality in developing and developed countries. Endothelial dysfunction, characterized by a decline in nitric oxide production and/or bioavailability, increased oxidative stress, decreased prostacyclin levels, and a reduction of endothelium-derived hyperpolarizing factor is considered an important prognostic indicator of various CVD. Changes in cyclic nucleotides production and/ or signalling, such as guanosine 3', 5'-monophosphate (cGMP) and adenosine 3', 5'-monophosphate (cAMP), also accompany many vascular disorders that course with altered endothelial function. Phosphodiesterases (PDE) are metallophosphohydrolases that catalyse cAMP and cGMP hydrolysis, thereby terminating the cyclic nucleotide-dependent signalling. The development of drugs that selectively block the activity of specific PDE families remains of great interest to the research, clinical and pharmaceutical industries. In the present review, we will discuss the effects of PDE inhibitors on CVD related to altered endothelial function, such as atherosclerosis, diabetes mellitus, arterial hypertension, stroke, aging and cirrhosis. Multiple evidences suggest that PDEs inhibition represents an attractive medical approach for the treatment of endothelial dysfunction-related diseases. Selective PDE inhibitors, especially PDE3 and PDE5 inhibitors are proposed to increase vascular NO levels by increasing antioxidant status or endothelial nitric oxide synthase expression and activation and to improve the morphological architecture of the endothelial surface. Thereby, selective PDE inhibitors can improve the endothelial function in various CVD, increasing the evidence that these drugs are potential treatment strategies for vascular dysfunction and reinforcing their potential role as an adjuvant in the pharmacotherapy of CVD.

Background: Prospective cohort studies and randomized controlled trials have shown the protective effect of n-3 fatty acids against cardiovascular disease (CVD). The effect of n-3 fatty acids on vascular endothelial cells indicates their possible role in CVD prevention. Objective: Here, we describe the effect of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) on endothelial dysfunction-caused by inflammation and oxidative stress-and their role in the development of CVD. Methods: We reviewed epidemiological studies done on n-3 fatty acids in CVD. The effect of DHA and EPA on vascular endothelial cells was examined with regard to changes in various markers, such as arteriosclerosis, inflammation, and oxidative stress, using cell and animal models. Results: Epidemiological studies revealed that dietary intake of EPA and DHA was associated with a reduced risk of various CVDs. EPA and DHA inhibited various events involved in arteriosclerosis development by preventing oxidative stress and inflammation associated with endothelial cell damage. In particular, EPA and DHA prevented endothelial cell dysfunction mediated by inflammatory responses and oxidative stress induced by events related to CVD. DHA and EPA also increased eNOS activity and induced nitric oxide production. Conclusion: The effects of DHA and EPA on vascular endothelial cell damage and dysfunction may involve the induction of nitric oxide, in addition to antioxidant and anti-inflammatory effects. n-3 fatty acids inhibit endothelial dysfunction and prevent arteriosclerosis. Therefore, the intake of n-3 fatty acids may prevent CVDs, like myocardial infarction and stroke.

Background: Cadmium is a worldwide spread toxicant that accumulates in tissues and affects many organs, mainly through oxidative damage. Oxidative stress is often associated with cardiovascular diseases and, when it affects vessels, it induces endothelial dysfunction, which, in turn, could precipitate atherosclerosis and hypertension. Therefore, it is reasonable to suggest antioxidant supplementation as a therapy against cadmiuminduced endothelial dysfunction. Objective: This literature review aims to present the mechanisms involving oxidative stress in which cadmium induces endothelial dysfunction and the benefits of antioxidant supplementation as a therapeutic strategy against its harmful effects. Methods: On PubMed Central, articles that contemplated studies on cadmium intoxication and associated oxidative stress with endothelial dysfunction as well as articles that reported the use of antioxidant supplementation in an attempt to prevent or avoid endothelial dysfunction induced by cadmium exposure were selected. Results: Most of the studies that associated cadmium intoxication with endothelial dysfunction suggested oxidative stress as the major mechanism for this damage. Furthermore, experimental studies also revealed that the administration of substances with antioxidant properties, such as ascorbic acid and curcumin, has beneficial effects on the prevention of such dysfunction, reducing reactive oxygen species within the vessels, preventing a reduction in the amount of glutathione and the increase in blood pressure observed in animals exposed to cadmium. Conclusion: Antioxidant therapy demonstrated to be a potential treatment to reduce cardiovascular injuries provoked by cadmium, but more studies are needed to determine the best antioxidant substance and dose to treat or avoid this complication.

The aim of the present work is to review the potential beneficial effects of dietary supplementation with bioactive egg protein hydrolysates or peptides on cardiometabolic changes associated with oxidative stress. The development of nutritionally improved food products designed to address specific health concerns is of particular interest because many bioactive food compounds can be potentially useful in various physiological functions such as for reducing oxidative stress. The results presented suggest that egg hydrolysates or derived peptides could be included in the diet to prevent and/or reduce some cardiometabolic complications associated with oxidative stress-related diseases.

Background: Punica granatum L. is an infructescence native of occidental Asia and Mediterranean Europe, popularly referred to as pomegranate. It has been used in ethnomedicine for several applications, including the treatment of obesity, inflammation, diabetes, and the regulation of blood lipid parameters. Thus, pomegranate has been linked to the treatment of cardiovascular diseases that have endothelial dysfunction as a common factor acting mainly against oxidative stress due to its high polyphenol content. Its biocomponents have antihypertensive, antiatherogenic, antihyperglycemic, and anti-inflammatory properties, which promote cardiovascular protection through the improvement of endothelial function. Methods: Different electronic databases were searched in a non-systematic way to uncover the literature of interest. Conclusion: This review article presents updated information on the role of pomegranate in the context of endothelial dysfunction and cardiovascular diseases. We have shown that pomegranate, or rather its components (e.g., tannins, flavonoids, phytoestrogens, anthocyanins, alkaloids, etc.), have beneficial effects on the cardiovascular system, improving parameters such as oxidative stress and the enzymatic antioxidant system, reducing reactive oxygen species formation and acting in an anti-inflammatory way. Thus, this review may contribute to a better understanding of pomegranate's beneficial actions on endothelial function and possibly to the development of strategies associated with conventional treatments of cardiovascular diseases.

The mechanisms responsible for cardiovascular and neurodegenerative diseases have been the focus of experimental and clinical studies for decades. The relationship between the gut microbiota and the organs and system tissues represents the research field that has generated the highest number of publications. Homeostasis of the gut microbiota is important to the host because it promotes maturation of the autoimmune system, harmonic integrative functions of the brain, and the normal function of organs related to cardiovascular and metabolic systems. On the other hand, when a gut microbiota dysbiosis occurs, the target organs become vulnerable to the onset or aggravation of complex chronic conditions, such as cardiovascular (e.g., arterial hypertension) and neurodegenerative (e.g., dementia) diseases. In the present brief review, we discuss the main mechanisms involved in those disturbances and the promising beneficial effects that have been revealed using functional food (nutraceuticals), such as the traditional probiotic Kefir. Here, we highlight the current scientific advances, concerns, and limitations about the use of this nutraceutical. The focus of our discussion is the endothelial dysfunction that accompanies hypertension and the neurovascular dysfunction that characterizes ageing-related dementia in patients suffering from Alzheimer's disease.

Background: Endothelial dysfunction is commonly present in estrogen-deficient states, e.g., after menopause. In the search for alternatives to hormone replacement therapy (HRT), treatments based on phytoestrogens or in non-hormonal mechanisms have been under evaluation. Objective: Here we aim to present an overview of innovative potential treatments for endothelial dysfunction in estrogen-deficient states, introducing our own preliminary data about the probiotic kefir. Methods: We conducted a review based on a PubMed database search for keywords of interest (Menopause, Ovariectomy, Vascular dysfunction, Hot flashes, Metformin, Statins, Phytoestrogens, Omega-3, Vitamin D, Probiotics). Results: Vascular parameters were found to be improved by both metformin and statins through pleiotropic effects, being related to a decrease in oxidative stress and restoration of the nitric oxide pathway. Phytoestrogens such as genistein and resveratrol have also been shown to improve vascular dysfunction, which seems to involve their estrogenic-like actions. Omega-3, vitamin D and its analogues, as well as probiotics, have shown similar vascular beneficial effects in both postmenopausal women and an animal model of ovariectomy (OVX), which could be related to antioxidant and/or anti-inflammatory effects. Moreover, our preliminary data on the probiotic kefir treatment in OVX rats suggested a vascular antioxidant effect. In particular, some evidence points to statins and vitamin D having anti-atherogenic effects. Conclusion: Pleiotropic effects of common medications and natural compounds could have therapeutic potential for endothelial dysfunction in estrogen-deficient states. They could, therefore, work as future complementary or alternative treatments to HRT.

The endothelium produces many substances that can regulate vascular tone. Acetylcholine is a widely used pharmacological tool to assess endothelial function. In general, acetylcholine binds to G-protein coupled muscarinic receptors that mediate a transient elevation in intracellular, free calcium. This intracellular rise in calcium is responsible for triggering several cellular responses, including the synthesis of nitric oxide, endothelium- derived hyperpolarizing factor, and eicosanoids derived from arachidonic acid. Endothelial arachidonic acid metabolism is also an important signaling pathway for mediating inflammation. Therefore, in conditions with sustained and excessive inflammation such as hypertension, arachidonic acid serves as a substrate for the synthesis of several vasoconstrictive metabolites, predominantly via the cyclooxygenase and lipoxygenase enzymes. Cyclooxygenase and lipoxygenase products can then activate G-protein coupled receptors expressed on vascular smooth muscle cells to causes contractile responses. As a result, acetylcholine-induced contraction due to arachidonic acid is a commonly observed feature of endothelial dysfunction and vascular inflammation in hypertension. In this review, we will critically analyze the literature supporting this concept, as well as address the potential underlying mechanisms, including the possibility that arachidonic acid signaling is diverted away from the synthesis of pro-resolving metabolites in conditions such as hypertension.

The endothelium has a crucial role in proper hemodynamics. Inflammatory bowel disease (IBD) is mainly a chronic inflammatory condition of the gastrointestinal tract. However, considerable evidence points to high cardiovascular risk in patients with IBD. This review positions the basic mechanisms of endothelial dysfunction in the IBD setting (both clinical and experimental). Furthermore, we review the main effects of drugs used to treat IBD in endothelial (dys)function. Moreover, we leave challenging points for enlarging the therapeutic arsenal for IBD with new or repurposed drugs that target endothelial dysfunction besides inflammation.

Endothelial dysfunction and consequent vasoconstriction are a common condition in patients with hypertension and other cardiovascular diseases. Endothelial cells produce and release vasodilator substances that play a pivotal role in normal vascular tone. The mechanisms underlying endothelial dysfunction are multifactorial. However, enhanced reactive oxygen species (ROS) production and consequent vasoconstriction instead of endothelium-derived relaxant generation and consequent vasodilatation contribute to this dysfunction considerably. The main targets of the drugs that are currently used to treat vascular diseases concerning enzyme activities and protein functions that are impaired by endothelial nitric oxide synthase (eNOS) uncoupling and ROS production. Nitric oxide (NO) bioavailability can decrease due to deficient NO production by eNOS and/or NO release to vascular smooth muscle cells, which impairs endothelial function. Considering the NO cellular mechanisms, tackling the issue of eNOS uncoupling could avoid endothelial dysfunction: provision of the enzyme cofactor tetrahydrobiopterin (BH4) should elicit NO release from NO donors, to activate soluble guanylyl cyclase. This should increase cyclic guanosine-monophosphate (cGMP) generation and inhibit phosphodiesterases (especially PDE5) that selectively degrade cGMP. Consequently, protein kinase-G should be activated, and K+ channels should be phosphorylated and activated, which is crucial for cell membrane hyperpolarization and vasodilation and/or inhibition of ROS production. The present review summarizes the current concepts about the vascular cellular mechanisms that underlie endothelial dysfunction and which could be the target of drugs for the treatment of patients with cardiovascular disease.

Endothelial dysfunction is a hallmark of type 2 diabetes that can have severe consequences on vascular function, including hypertension and changes in blood flow, as well as exercise performance. Because endothelium is also the barrier for insulin movement into tissues, it acts as a gatekeeper for transport and glucose uptake. For this reason, endothelial dysfunction is a tempting area for pharmacological and/or exercise intervention with insulin-based therapies. In this review, we describe the current state of drugs that can be used to treat endothelial dysfunction in type 2 diabetes and diabetes-related diseases (e.g., obesity) at the molecular levels, and also discuss their role in exercise.

In addition to the endothelium, the perivascular adipose tissue (PVAT) has been described to be involved in the local modulation of vascular function by synthetizing and releasing vasoactive factors. Under physiological conditions, PVAT has anticontractile and anti-inflammatory effects. However, in the context of hypertension, obesity and type 2 diabetes, the PVAT pattern of anticontractile adipokines is altered, favoring oxidative stress, inflammation and, consequently, vascular dysfunction. Therefore, dysfunctional PVAT has become a target for therapeutic intervention in cardiometabolic diseases. An increasing number of studies have revealed sex differences in PVAT morphology and in the modulatory effects of PVAT on endothelial function and vascular tone. Moreover, distinct mechanisms underlying PVAT dysfunction may account for vascular abnormalities in males and females. Therefore, targeting sex-specific mechanisms of PVAT dysfunction in cardiovascular diseases is an evolving strategy for cardiovascular protection.