34. Anti-Stroke Action of Olive Polyphenols
Of all neurological disorders, cerebrovascular diseases are responsible for more than half of the burden and 85% of the deaths related to neurological diseases worldwide. Stroke was the second leading cause of death, for about 143 million people, worldwide in 2019, with numbers expected to increase by 2030
[23].
3.1. Olive Polyphenols and Hypertension
4.1. Olive Polyphenols and Hypertension
Hypertension is one of the most common disorders and, more importantly, is the main risk factor for cerebral insult. Due to high intraluminal pressure, the endothelium and smooth muscle in intracerebral arteries are exposed to increased stress leading to structural changes within the vessel wall. This leads not only to local thrombus formation, stenosis, occlusion, and ischemic lesions but also to the arteriosclerotic process. In other words, it leads to degenerative changes in smooth muscle cells and the endothelium, resulting in increased arterial stiffness associated with an increased risk of stroke
[39][40][80,81]. Furthermore, all these changes lead to endothelial dysfunction and inadequate compensatory mechanisms unable to protect microvessels from increased pressure
[41][82]. This also accelerates ischemic attacks and cerebral infarcts or predisposes the subject to plasma extravasation and focal cerebral edema, lacunar infarcts, and intracerebral hemorrhage
[42][43][83,84].
The vascular endothelium plays an important role in regulating vascular tone through the synthesis of NO, prostaglandins, and other relaxing factors and provides protection against oxidative, inflammatory, thrombotic, and atherosclerotic processes, thus serving as a controller of normal blood pressure
[44][45][85,86]. The essential homeostatic processes regulated by the endothelium are modulated by crosstalk between endothelial cells and other vascular cell types, including smooth muscle cells, monocytes, and macrophages, which contribute to normal vascular function. However, impaired communication between endothelial cells and these vascular cell types has been associated with vascular dysfunction and pathological remodeling in hypertension, atherosclerosis, atherothrombosis, and other cardiovascular diseases
[46][87].
Endothelial dysfunction may also precede the development of hypertension by contributing to increased peripheral resistance, i.e., through activation of the renin–angiotensin system, endothelin-1, catecholamines, and growth factors’ production
[41][47][82,88]. In addition, the induction of inflammatory processes and the production of ROS in the vessel wall may be associated with endothelial dysfunction. ROS are key signaling molecules through which vasoactive agents such as angiotensin II, endothelin-1, and others modify cell function through highly-regulated, redox-sensitive signal transduction. ROS stimulate multiple signaling pathways involved in inflammation and vascular remodeling (NF-κB, MAPK, JAK-2, STAT, etc.) and thus are involved in the development of hypertension
[44][85].
There are many studied antihypertensive mechanisms of olive polyphenols, and yet this is only the beginning of a larger picture. Sustained consumption of phenolic-enriched virgin olive oil with different polyphenols causes improvements in endothelial function in humans
[48][89]. The antihypertensive effects of olive oil and olive leaves are mainly attributed to the main phenolic compounds that reduce blood pressure through a number of specific mechanisms. Oleuropein is the most commonly described polyphenolic compound. A large number of studies in humans and laboratory rats have demonstrated its antihypertensive activity
[49][50][90,91]. Olive leaf polyphenols have been shown to lower diastolic and systolic blood pressure in prehypertensive and hypertensive groups of patients
[51][52][53][54][55][56][92,93,94,95,96,97].
The beneficial effects that olive oil and leaf phenolic compounds may have on endothelial function include the inhibition of monocyte adhesion and platelet activation, improvement in vasodilation
[25] through the modulation of potent vasodilator and vasoconstrictor agents such as NO and endothelin-1 (ET-1)
[57][98], and, furthermore, through the expression of their antioxidant and anti-inflammatory activity
[56][58][97,99]. As stated earlier, all of these mechanisms of action are involved in the development of hypertension if not prevented or treated beforehand. The best known anti-inflammatory effects of olive polyphenols that can prevent endothelial dysfunction and progressive vasoconstriction include the inhibition of transcription factors NF-kB and AP-1, and the reduction in vascular TLR4 expression by the inhibition of mitogen-activated protein kinase (MAPK) signaling with the subsequent reduction in pro-inflammatory cytokines (IL-6, IL-10, TNF-α, IL-1β, etc.) and inflammatory markers (COX-2, PGE2, etc.)
[6][59][60][61][6,100,101,102]. The novel anti-inflammatory effects of olive polyphenols hydroxytyrosol and oleuropein are thought to result from the suppression of phosphorylation and release of platelet heat shock protein 27, an extracellular pro-inflammatory agent
[62][103]. As mentioned earlier, the antioxidant effects of olive polyphenols include upregulation of the expression of antioxidant enzymes (glutathione peroxidase (GPx), glutathione disulfide reductase (GSR), SOD-1, etc.), the elimination of elevated superoxide levels, the reduction in increased NADPH oxidase activity, and the activation of antioxidant cell proteins such as SIRT1 and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α)
[25][63][64][65][25,104,105,106]. Moreover, olive leaf polyphenolic compounds oleuropein and hydroxytyrosol are efficient cytoprotective agents against H
2O
2-induced oxidative stress and toxicity in human umbilical vein endothelial cells
[66][107].
In a study by Choi et al.
[67][108], treatment with oleuropein significantly increased an angiotensin II-induced decrease in the levels of peroxiredoxin (Prdx)-1 and -2 in vascular progenitor cells, which have an important antioxidant and protective function in cells. By regulating the expression of Prdx-1 and Prdx-2 and by activating the ERK1/2 phosphorylation cascade, oleuropein decreases cellular ROS levels and reduces oxidative stress. Hydroxytyrosol and tyrosol from olive mill wastewater, a by-product of olive oil processing, also showed potent antioxidant capabilities to counteract H
2O
2-induced oxidative stress and cell death in cell viability experiments that included endothelial cells and vascular smooth muscle cells
[68][109].
In animal models of simultaneous renal hypertension and type 2 diabetes associated with the impaired release of NO, oleuropein showed sympathoplegic activities with subsequent lowering of systolic blood pressure. In addition to lowering systolic blood pressure, it also decreased the maximal response to phenylephrine and increased the maximal response to acetylcholine
[69][110].
The antihypertensive effects of oleuropein can be seen by its negative chronotropic and inotropic effects on the heart
[70][111]. This effect could be of great importance in isolated systolic hypertension. Moreover, virgin olive oil has been shown to have an inhibitory effect on angiotensin-converting enzyme (ACE) and thus to have a vasodilatory effect in spontaneously hypertensive rats
[71][72][112,113]. Overall, olive polyphenols have a beneficial effect on cardiovascular parameters, including sequels of hypertensive disorder such as heart failure, myocardial infarction, and renal hypertension
[25][26][27][25,26,27].
Many studies have confirmed the endothelium-dependent vasorelaxant effect of olive polyphenols. As previously mentioned, NO is an important protective molecule in the vascular system, and endothelial NO synthase (eNOS) is responsible for most of the vasodilatory NO production
[73][114]. Olive phenolic compounds perform a particular task to increase NO bioavailability and the expression of eNOS
[74][115]. an imbalance between NO and ET-1 leads to endothelial dysfunction, and it is possible that hyperglycemia and hyperlipidemia may decrease endothelial NO synthase phosphorylation and, consequently, intracellular NO levels and increase ET-1 synthesis. Hydroxytyrosol and extra virgin olive oil polyphenol extract partially reverse these abnormalities
[57][98]. In addition, it was observed that hyperglycemia and free fatty acids decreased NO and increased acetylcholine-induced ET-1 levels by modulating intracellular calcium concentrations and endothelial NO synthase phosphorylation, events that were also reversed by hydroxytyrosol and the polyphenol extract
[57][98]. Moreover, simple phenols from extra virgin olive oil, tyrosol, and hydroxytyrosol can modulate the NO balance by decreasing its degradation (through decreased superoxide formation) and increasing its production through the Akt1/eNOS pathway
[75][116].
Another possible mechanism by which oleuropein exerts the antihypertensive effect is by affecting renal water reabsorption in renal cells, i.e., by preventing vasopressin-induced aquaporin-2 translocation to the plasma membrane of renal cells
[76][117]. In addition to diuresis, it also has a stimulating effect on natriuresis
[77][118].
3.2. Olive Polyphenols and Vascular Dysfunction
4.2. Olive Polyphenols and Vascular Dysfunction
Vascular dysfunction includes large artery dysfunction due to arterial stiffness, microvascular dysfunction (dysfunction of the microcirculation), and endothelial dysfunction (dysfunction of the endothelium)
[78][119]. Arterial wall stiffening is determined by the reduced elastin–collagen ratio caused by the production of ROS and by inflammation, aging, hypertension, hyperglycemia, and dyslipidemia; all mechanisms that olive polyphenols reduce and counteract. In addition, arterial stiffness due to decreased compliance of the large peripheral arteries leads to increased pulsatile pressure and blood flow stress, which damage the cerebral microcirculation. Cerebral capillaries are particularly vulnerable to this damage due to low impedance, which can lead to a reactive increase in vascular resistance and subsequent impaired vasoreactivity and microvascular ischemia
[79][120]. Olive polyphenol ingestion may help prevent these cerebral disorders, and thus cerebral stroke, by reducing blood pressure and associated endothelial dysfunction, and the occurrence of arterial stiffness. Arterial stiffness and endothelial dysfunction are distinct aspects of vascular disease, but there is certainly a crosstalk between these two pathophysiological processes
[80][121]. As mentioned earlier, endothelial dysfunction is characterized by an imbalance between vasoconstrictor and vasodilator factors, by increased levels of ROS and pro-inflammatory factors, and by decreased NO secretion. All these lead to increased vasoconstriction, leukocyte adhesion, smooth muscle cell proliferation, extracellular matrix deposition, cell adhesion, platelet activation, prooxidation, thrombosis, impaired coagulation, vascular inflammation, and atherosclerosis
[45][81][86,122].