Flavanols and Cardiovascular Disease Prevention

Christian Heiss; Carl L. Keen; Malte Kelm

Disclosures

Eur Heart J. 2010;31(21):2583-2592. 

In This Article

Potential Mechanisms Contributing to Flavanol-induced changes in Endothelial Vascular Health: Experimental Evidence

The mechanisms by which flavanols mediate their vascular effects are not fully understood. As supported by clinical data, animal, and in vitro studies, short-term effects may be related to an increase in NOS activity.[24] The precise mechanism and biological target structure(s) or receptor(s) have not been identified in vivo. Besides direct effects on eNOS, inhibitory effects on pathways that may negatively affect NOS activity including NADPH oxidase, ACE, ADMA, and endothelin-1 have been proposed to be affected by flavanols.[24]

The oral administration of flavanol-rich food extracts (red wine polyphenol extract over 7–10 days) or the flavanol monomer catechin to rats led to increased acetylcholine NOS-dependent vasodilation, NO production, and decreased superoxide (O2−.) production of aortic rings isolated from these animals along with a significant decrease in blood pressure.[79,80] These results were corroborated by Ramirez-Sanchez et al.[81] showing that nano-micromolar concentrations of (−)-epicatechin acutely stimulate eNOS activity in human coronary endothelial cells and a membrane bound acceptor was proposed. Schnorr et al. reported that (−)-epicatechin, as well as select metabolites of cocoa flavanols, inhibits the expression of arginase-2 in cultured endothelial cells. An effect of flavanols on arginase was also demonstrated in vivo, providing evidence that a flavanol-rich intervention can result in an inhibition of arginase activity in human red blood cells and rat kidney ex vivo.[82] These data suggest flavanols have the potential to increase NOS activity by increasing the availability of the substrate L-arginine. Notably, mono methylated flavanol metabolites were shown to enhance NO bioactivity by attenuating its degradation via O2.[24] In a cell culture model, Steffen et al.[24] reported that 3′-O-methyl-epicatechin is a bioactive metabolite of epicatechin that can inhibit NADPH oxidase, reducing O2−. generation through this system. The authors reported that, under these conditions, there was an increase in steady-state NO levels as indicated by DAF-2DA fluorescence. The authors reported that the methylation of epicatechin in endothelial cells is required to inhibit angiotensine II mediated increases in NADPH oxidase dependent O2−. formation. However, this mechanism has yet to be demonstrated in vivo. Endothelins (ETs), a family of vasoactive peptides, are rapidly produced by endothelial cells in response to tissue injury and play a major role in vascular dysfunction and vascular disease.[83] Whereas (−)-epicatechin did not inhibit ET-1 synthesis in vitro, oral application of epicatechin lowered ET-1 levels along with increasing NO species in healthy human subjects.[63,84] Together with the results from studies showing that aortic rings do not dilate in the presence of flavanol monomers,[85] the partly discrepant results from in vitro and in vivo systems imply that flavanol metabolites, rather than the parent molecule, trigger many of the critical biological activities that are pertinent with respect to vascular health.

In the context of long-term effects, general patterns of cellular adaptive or regenerative responses have to be considered on the overall tissue/organ level as well as on an individual cell level with the eNOS axis likely being only one of the pathways involved. Based on the results from murine models, it has been suggested that the regular ingestion of flavanols and flavanol extracts can inhibit aortic plaque size by up to 40%,[86] inhibit the expression of inflammatory cytokines, and reduce I/R injury with a 30% reduction in infarct size.[87]

While the above mechanistic work is of interest, several limitations have to be kept in mind when evaluating experimental studies aiming at understanding the mechanisms by which flavanols mediate their vascular effects. With respect to in vitro models, including cell culture systems and isolated vessel systems such as aortic rings, limitations include the relevance of flavanol compounds that are used (e.g. parent compounds vs. metabolites), and the concentrations of the flavanol/flavanol metabolite used in the experimental system. Regarding the relevance of flavanol compounds used in experimental set-ups, flavanol absorption and metabolism need to be considered and accounted for. As noted above, the majority of 'flavanols' present in most foods, such as cocoa are present as oligomers (procyanidins), rather than monomers, and it is now well established that to a great extent only the monomers and dimers are absorbed. Thus, one needs to carefully evaluate the data obtained from in vitro studies when longer oligomers, and whole food extracts, are added to the media,[85,88] particularly in the context of cardiovascular research. Furthermore, monomers, which are absorbed, are rapidly metabolized. Thus, in plasma, following absorption, the parent molecule (−)-epicatechin (~5–250 nM) represents a minor portion of total plasma flavanols (<3 uM), yet, the biological effects of the major classes of epicatechin metabolites, including methylated, glucuronidated, and sulfated adducts have received only limited study to date.[89] As noted above, 3′-O methyl epicatechin can be an inhibitor of NADPH oxidase and may thereby enhance NO bioactivity in vitro (ref.[24] and references herein). Schewe et al.[24] hypothesized that flavanol glucuronides serve as water soluble transport forms of flavanols in blood that can be cleaved by endothelial β-glucuronidase and then stored as agycones. A second major limitation of many experimental studies is the high concentration of flavanols used in them. Plasma concentrations of physiological flavanol metabolites are in the nanomolar and low-micromolar range, whereas many in vitro studies have been performed in the micromolar range. In this context another layer of complexity has to be taken into account. Aglycone epicatechin, due to its high protein binding, is rapidly taken up by cells.[90] A third major limitation of experimental work relates to the question as to whether the experimental system is relevant for human physiology or disease. Results obtained on the cellular level need to be considered in concert with meaningful in vivo read-outs of a physiological response in appropriate animal models, and linked back to clinically relevant human models.

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as:

processing....