Flavonoid-Rich Grapeseed Extracts: A New Approach In High Cardiovascular Risk Patients?

P. Kar; D. Laight; K. M. Shaw; M. H. Cummings

Disclosures

Int J Clin Pract. 2006;60(11):1484-1492. 

In This Article

The 'Complex' Linkage

Stern proposed the Common Soil hypothesis[1] in 1995 (linking atherosclerosis, inflammation and the metabolic syndrome) and there has been an abundance of evidence linking these conditions and the complex pathophysiology underlying the metabolic syndrome.

The vascular endothelium plays a key role in the regulation of vascular homeostasis and increasing evidence suggests that alterations in endothelial function contribute to the pathogenesis and clinical expression of cardiovascular disease.[2] Endothelial cells regulate vascular homeostasis by producing factors that act locally in the vessel wall and lumen, and a key endothelial product is nitric oxide (NO). Impaired NO production, increase in peroxynitrite formation, a pro-inflammatory milieu, and endothelial damage are some of the mechanisms leading to impaired vasodilatory capacity and endothelial dysfunction. In 1999, Duffy et al. revealed the importance of endothelial functional integrity in atherosclerosis and coronary ischaemia.[3] Atherosclerosis was seen to be dependent upon metabolic vasodilation via tonic release of endothelial NO and vasodilator prostanoids.[4]

Abnormal endothelial function is however often portrayed as a simple reduction in NO-mediated endothelium-dependent vasodilator responses, when this is just one feature of a more complex pattern of changes. Indeed, as vasodilator function decreases, there is increased vasoconstriction due to excess endothelin-1 (ET-1) synthesis[5,6] and other vasoconstricting agents. These alterations in vascular tone are coincident with a spectrum of pro-inflammatory and pro-thrombotic vascular changes. Endothelial dysfunction is now considered important both as a target and mediator in high cardiovascular risk patients such as type 2 diabetes.[7,8]

Oxidative stress has a deleterious effect upon endothelial function[9] and is a major culprit in the complex web of factors propagating the syndrome of insulin resistance and type 2 diabetes mellitus (DM).[7] Unsurprisingly, this has prompted a great deal of research and investigations looking at the effects of antioxidants on endothelial function, because of the therapeutic modality of reducing oxidative stress.

Atherosclerosis and the Role of Oxidative Stress upon Endothelial Function

Atherosclerosis is a chronic inflammatory disease that develops in lesion-prone regions of medium-sized arteries. As is well known, they may be present and clinically silent for decades before becoming active and producing clinical events such as cardiac death and cerebrovascular events.

Atherosclerosis can be taken as an example of a process for which there is substantial evidence of the effect of oxidative stress. Hypercholesterolaemia is universally accepted as a major risk factor for atherosclerosis. However, at any given concentration of plasma cholesterol, there is still great variability in the occurrence of cardiovascular events. One of the major breakthroughs in atherogenesis research has been the realisation that oxidative modification of low-density lipoprotein (LDL) might be a crucially important step in the development of the atherosclerotic plaque.[10,11] Native LDL causes the formation of foam cells from monocyte-derived macrophages in early atherosclerotic lesions only after the modification of LDL by various chemical reactions such as oxidation. As oxidation of LDL is primarily a free radical-mediated process that is inhibited by antioxidants, antioxidant depletion might be a risk factor for cardiovascular disease. Inactivation of endothelium-derived vasodilator NO is caused by vascular superoxide anion.[9,12] Nitric oxide combines with superoxide intravascularly to create peroxynitrite, a cytotoxic molecule, which then oxidises LDL.[13]

Evidence for LDL oxidation in vivo is now well established. In immunocytochemical studies, antibodies against oxidised LDL stain atherosclerotic lesions but not normal arterial tissue.[14] In young survivors of myocardial infarction (MI), an association has been demonstrated between increased susceptibility of LDL to oxidation and the degree of coronary atherosclerosis, whereas the presence of ceroid, a product of lipid peroxidation, has been shown in advanced atherosclerotic plaques.[15]

Apart from the atherogenic consequences of LDL oxidation, it is increasingly recognised that reactive oxygen and nitrogen species directly interact with signalling mechanisms in the arterial wall to regulate vascular function.[16]

The effects of antioxidants on these processes are complex but provide alternative mechanisms by which antioxidant supplementation might ameliorate vascular pathology, for instance by improving endothelial function.

Evidence suggests that the balance between pro-oxidant properties of peroxynitrite formed from NO and antioxidant properties of plasma[17] and NO[18] determines the progression of pathology in atherosclerosis.

The Role of Inflammation in the Metabolic Syndrome

In recent years inflammation has also been found to play a key role in the causation of atherosclerotic changes and C-reactive protein (CRP) has been deemed as an important biological marker of inflammation that has been linked to cardiovascular disease.[19] Profound interest has been generated in inflammation being a mediator in insulin resistance and furthermore in the pathogenesis and complications of type 2 diabetes.[20]

Current evidence suggests that oxidative stress, insulin resistance, endothelial dysfunction (in the peripheral arterial bed) and more recently inflammation might be acting synergistically, to promote the development of the metabolic syndrome and subsequent pathology.[21,22] Chronic subclinical inflammation is widely being recognised as a key component in the aetiology of macrovascular disease and possibly even the metabolic syndrome and type 2 diabetes [Insulin Resistance & Atherosclerosis (IRAS) study].[23] A rise in inflammatory markers (CRP, fibrinogen and white cell count) in conjunction with insulin resistance was demonstrated in the IRAS study. Similarly Ridker et al.[24] have shown a strong association between elevated CRP and atherosclerosis and also elevation in CRP and interleukin (IL)-6 levels being predictive of development of diabetes.[25] Clapp et al.[26] showed that inflammation can cause endothelial dysfunction, reduce vascular NO bioavailability and increase oxidative stress, which may alternatively suggest inflammation as the initiating factor. In this study, basal and stimulated endothelial NO bioavailability were measured, while systemic effects were determined by measuring cytokine response, total antioxidant status and urinary protein excretion.

The Importance of Nuclear Factor-κB

Nuclear factor-κB (NF-κB) is an inducible eukaryotic transcription factor of the rel family, which is critical in regulating transcription of specific genes, most of which, are involved in the immune, inflammatory responses and infection and induction of various agents including IL-1 and IL-6, and adhesion molecules. Research has shown an increase in NF-κB activation leads to a proinflammatory state (27) giving rise to suggestions that a decrease in this parameter might positively affect the pathophysiology of the metabolic syndrome. Examples of this are borne out by the effect of antioxidant and anti-inflammatory properties of glitazones,[28] while high-dose aspirin has also been said to have a similar effect on glucose metabolism in type 2 diabetes.[29] NF-κB acts as a transcription factor for various proteins including VCAM-1 and ELAM-1, which are responsible for monocyte adhesion to endothelium[30] - an initial trigger in the formation of atheroma.

Ochnoflavone, a naturally occurring bioflavonoid is thought to inhibit NF-κB due to its inhibition of lipopolysaccharide-induced NO formation - which may be the basis for its anti-inflammatory effects.[31] Recent research has also suggested flavonoid-rich products such as apple extracts[32] and green tea[33] to downregulate NK-κB signalling, thereby possibly reducing the pro-inflammatory state.

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