Study Title:

Resveratrol as a Main-Line Therapy for Cardio Health

Study Abstract

Natural health products (NHP) which include minerals, vitamins and herbal remedies are not generally considered by medical practitioners as conventional medicines and as such are not frequently prescribed by health centre's as either main-line or supplemental treatments. In the field of cardiovascular medicine, studies have shown that typically, less than half of patients suffering from coronary syndromes chose to take any form of NHP supplement and these products are rarely recommended by their medical practitioner. Vascular/endothelial cell damage is a key instigator of coronary arterial plaque development which often culminates in thrombosis and myocardial infarction (MI). Current treatment for patients known to be at risk of primary or secondary (MI) includes lipid lowering statins, anti-clotting agents (e.g. tissue plasminogen activator; tPA) and drugs for stabilization of blood pressure such as betablockers. However, evidence has been building which suggests that components of at least several NHP (e.g. aged garlic extract (AGExt), resveratrol and green tea extracts (GTE)) may have significant vascular protective effects through reduction of oxidative stress, lowering of blood pressure, reduction in platelet aggregation, vasodilation and inhibition of abnormal angiogenesis. Therefore, in this review we will discuss in detail the potential of these substances (chosen on the basis of their potency and complimentarity) as anti-atherosclerotic agents and the justification for their consideration as main-line additional supplements or prescriptions.

Trans-resveratrol, a polyphenol, and the major grapevine phytoalexin (3,5,4´- trihydroxystilbene; Figure 2) has attracted a lot of attention in the last couple of years due to its extremely potent anti-oxidative and anti-inflammatory capacity and its potential use in the treatment of vascular disease and prevention or attenuation of atherosclerosis [35]. This group of anti-oxidants is thought to be responsible for the ‘French paradox’ where a low mortality rate for CAD exists in the population despite their diet of high fat and smoking
[36]. In vitro and in vivo studies have identified a multitude of potentially protective effects of this compound. For example, Balestrieri et al., [37], demonstrated that resveratrol or indeed red wine alone could significantly prevent TNF-α-induced reduction in endothelial
cell progenitor (EPC) cell number at physiological concentrations which could positively impact on re-endothelization of damaged vessels. Resveratrol was also shown to block Ca2+ influx in thrombin-stimulated platelets and to block ADP, collagen and thrombin induced
platelet aggregation through a pathway which may involve inhibition of thromboxane A2 [38]. Similarly, resveratrol was shown to inhibit human platelet aggregation stimulated by collagen and concomitantly induce platelet apoptosis through activation of caspases-9, 3, and
8 as well as gelsolin and actin cleavage [39]. Prevention of aggregation coupled with apoptosis may represent an important mechanism for reduction in thrombotic events.

Figure 2 Schematic showing the structure of resveratrol and some of its most potent effects on intracellular signalling associated with prevention of EC activation and unstable plaque development. Its potent anti-oxidant, anti-inflammatory and EC protective effects are included here and are thought to be the main reason for its cardio-protective effects and ability to inhibit plaque de-stabilization Resveratrol also inhibited both endothelial cell migration and MCP-1-induced monocyte cell chemotaxis, which could potentially reduce neointimal vascularisation and monocyte recruitment into a growing plaque [40]. Regarding inflammation, roscovitine is a potent inhibitor of NF-κB activation, other inflammatory gene expression (e.g. IL-6, IL-8), endothelial cell adhesion molecule expression including ICAM-1 and monocyte adhesiveness to endothelial cells (and recruitment into the artery wall) in an Akt-dependent manner [35,41]. Resveratrol also inhibits cyclooxygenase and hydroperoxidase functions thereby reducing inflammation even more potently [42]. Using an apoE knockout mouse model, Norata et al. [43] showed that animals fed with a supplement containing cathechin, caffeic acid and resveratrol, had significantly smaller plaques after 8 weeks (36–40%) in the aortic sinus and ascending aorta mainly due to a reduction in inflammatory infiltration and expression of MCO-1, MIP-1α, MIP-1β, CCR1, CCR2 and ET1 in the vascular wall.

Similarly, Kim et al. [44] showed that oral administration of resveratrol suppressed intimal hyperplasia in a wire-injured femoral artery mouse model. Their further examination of cultured smooth muscle cells revealed inhibition of PDGF-induced ROS and cell
proliferation as well as increased expression of Nrf2 and anti-oxidant response element reporter activity associated with HO-1 induction. This data was in agreement with work performed by Brito et al., [45], who showed that resveratrol could inhibit oxLDL-induced
smooth muscle cell proliferation via inhibition of the PI3K/Akt/mTOR/p70S6K pathway. Endothelial cell function is known to be improved in the presence of resveratrol through potentiation of endothelial NO synthase (eNOS) via activation of PPARα and SIRT1 in
vascular endothelial cells and diabetic rats in vivo [38,46]. In monocytes from diabetic patients resveratrol, counteracted the pro-atherosclerotic effects of high glucose levels by reducing super-oxide production through activation of mitochondrial signalling pathways
involving SIRT1-FOXO. E-selectin was also down-regulated [47]. Studies with type-1 diabetic rats have shown that treatment with resveratrol (10 mg/kg) prevented impairment in eNOS and nNOS-dependent vasodilation in cerebral blood vessels. eNOS and nNOS were
also increased whilst super-oxide dismutase was reduced suggesting a restorative function for vascular tissue and oxidative stress [48]. Nitric oxide regulates vascular tone, causes endothelium-dependent vasodilation, and decreases platelet aggregation. In addition it acts as an anti-oxidant, anti-proliferative and anti-inflammatory molecule giving it a key role in the inhibition/prevention of atherosclerosis [49]. A multitude of studies have also shown a significant reduction in oxidative stress in a variety of cardiovascular-implicated cells
including blood mononuclear cells (decreased malondialdehyde concentration), human platelets (reduction in peroxynitrite-induced oxidation), super-oxide scavenging in damaged rat myocardial tissue and inhibition of LDL oxidation ([50] for a review).

Other studies show the enormous potential clinical applications of this compound from demonstrations of its complete lack of toxicity in humans even at high doses, to its lipid lowering capability in mammalian models and general ‘reduction in modifiable risk factors’
[51,52] and protection of cardiomyocytes against apoptosis [53].

Study Information

Slevin M, Ahmed N, Wang Q, McDowell G, Badimon L..
Unique vascular protective properties of natural products: supplements or future main-line drugs with significant anti-atherosclerotic potential?
Vasc Cell.
2012 April
Centro de Investigación Cardiovascular CSIC-ICCC Hospital de la Santa Creui Sant Pau, Pavelló del Convent Sant Antoni Maria Claret, 167 08025 Barcelona, Spain.

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