The first indications of a possible influence of Coenzyme Q10 on vascular functions go back to the late
1980s, when our group in Italy highlighted its mild, yet significant hypotensive effect, and this was evident both on systolic as well as on diastolic pressure (1). Several years later we started to study CoQ10 in blood. The presence of CoQ10 in white blood cells was not unexpected, as they contain a certain number of mitochondria, where CoQ10 is essential for energy production. It soon became evident that most of the CoQ10 in blood is not within the blood cells but in plasma, mainly associated with LDL. These are a well-‐ known class of lipoproteins, special complex particles which allow lipids, such as cholesterol, to be transported in plasma. Plasma is a rather aqueous environment and lipids (fats) do not mix well with water; the external part of LDL is very compatible with water, on the other hand their inner part is lipophilic, i.e. it well accommodates cholesterol and other fats.
Structure of LDL
Like all the other structures of our body also LDL are exposed to oxidative insult and oxidized LDL, which contain oxidized cholesterol, become appetizing targets for macrophages, a special class of cells which remove bacteria and defective molecules. These lipid-‐loaded macrophages, called foam cells, constitute the basis of atheroma, the thickening of the arterial wall which hampers blood circulation and at the same time constitutes a very vulnerable plaque which can trigger the formation of a blood clot blocking blood flow. When this happens in coronary arteries we have myocardial infarction. It was already known that higher amounts of LDL mean increased cardiovascular risk, and it is also true that more oxidizable, therefore more vulnerable, LDL also predispose for atherosclerosis; slowing down LDL oxidation might therefore delay the formation of atheroma.
Fig 1 shows the formation of foam cells
In the early 1990s Roland Stocker and his group discovered that the reduced form of CoQ10 i.e. ubiquinol-‐
10, is the most reactive antioxidant in LDL and is also capable of regenerating the active form of vitamin E, another potent antioxidant in these particles. Furthermore it was soon evident that oral supplementation with CoQ10, even for a few days, makes LDL more resistant to oxidation (2). In the following years different researchers, including our group, confirmed those data (3). Safeguarding LDL is only one of the protective effects of CoQ10 on our arteries. We also have other kinds of lipoproteins, among them HDL (high density lipoproteins) which play a defensive role, also by protecting LDL. We recently discovered (4) that CoQ10 supplementation also leads to increased CoQ10 content in HDL and enhanced defensive activity of these lipoproteins.
Fig 2 illustrates the different vulnerability to oxidative stress of native LDL and LDL enriched with
During the last two decades much research has addressed endothelial dysfunction. The endothelium is the inner lining of our arteries. This fundamental component of our blood vessels acts by releasing several vasoactive factors that are responsible for relaxation and contraction of arteries, inhibition of platelet aggregation (clot prevention) and smooth cell proliferation (also a cause of atheroma), and finally for exerting anti-‐inflammatory properties. Among the vasorelaxing factors, one of the most studied is nitric oxide (NO•). Endothelial dysfunction reflects an imbalance between release of vasodilator and vasoconstrictor endothelial-‐derived factors. A decrease in the availability of NO• involves either a decrease in its production by endothelial cells or in increased elimination of NO• itself. It is known that oxidative stress is one of the causes of NO• inactivation and superoxide anion is a molecular species responsible for it. Intercellular matrix, the material that holds endothelial cells together, is also endowed with defensive tools against NO• oxidation. These are mainly represented by extracellular superoxide dismutase (ecSOD), an enzyme which eliminates superoxide anion. Investigating this complex molecular scenario involves sophisticated biochemical methods which are not routinely performable. Endothelial function can be measured indirectly by assessing the vasodilatory response of peripheral arteries to stimuli that increase NO• release. One of the techniques consists in measuring flow-‐mediated dilation (FMD). Using a blood pressure cuff applied on the upper arm, blood flow is stopped for a few minutes: upon release of the cuff the sheer stress produced by resumed blood flow stimulates NO• production by endothelial cells. Upon NO• release there is an increase in the artery diameter which can be measured by an echograph. A decrease below the expected arterial dilation indicates endothelial dysfunction, which is predictive of adverse clinical events. CoQ10 positively affects FMD, mitigating endothelial dysfunction. The first
observation was made by Gerald Watts and his group, who a documented positive effect of CoQ10 in ameliorating FMD, and therefore endothelial dysfunction, in a group of Type II diabetes mellitus patients (5). In the same years intensive work started in Ancona, in cooperation with Dr. Belardinelli, focused on the effect of CoQ10 and physical exercise in patients affected by coronary heart disease This cooperation led to the publication of two papers, both in the European Heart Journal. In the first one (6) we studied the effect of physical exercise alone, CoQ10 with and without physical exercise, and placebo. It was already known that physical exercise improves endothelial dysfunction in patients affected by ischemic heart disease: CoQ10 supplementation was effective to the same extent and the combination of CoQ10 + exercise was even more impressive. In the second paper we confirmed the positive effect of CoQ10 in improving FMD in patients suffering from ischemic heart disease and we also discovered that CoQ10 also increases the amount of extracellular SOD (7). This effect was particularly evident in patients with more altered FMD.
It has been known for many years that CoQ10 improves some cardiac parameters in heart failure. A recent work (8) even showed that CoQ10, in combination with selenium, improves survival of these patients. From what we have been learning about the vascular action of CoQ10 we can reasonably hypothesize that these positive effects can be ascribed not only to ameliorating cardiac bioenergetics but also to a better function of the vessels, and in particular coronary arteries.
Endothelial function is also influenced by the inflammatory status of these cells, and ubiquinol affects these processes as well. During ageing, endothelium undergoes specific modifications characterized by enhanced inflammatory response and compromised NO•-‐producing activity. Very recently, we were able to study these processes at molecular level using an in vitro model of vascular ageing, i.e. a culture of endothelial cells grown in vitro until they reach senescence. This enabled us to evaluate the effect of CoQ10 in modulating inflammatory response associated with senescence. This was carried out in basal conditions and in the presence of an acute pro-‐inflammatory stimulus, i.e. the exposure to bacterial lipopolysaccharide (LPS)(9). In senescent endothelial cells the enhanced release of inflammatory markers is known to be activated by modulation of specific intracellular signalling processes regulated by small non coding RNA defined microRNA (miR). Exposure to ubiquinol of young cells challenged with LPS was able to silence inflammatory-‐associated signalling, effectively curbing cell release of interleukin-‐6, the main proinflammatory factor responsible for SASP (Senescence associated secretory phenotype). In older cells intracellular signalling was also quenched although this did not translate in a significant decrease of IL-‐6 release. This data is probably associated with an overly high inflammatory background in older cells.
Both resistance of LDL to peroxidation and endothelial function are positively influenced by plasma ubiquinol concentration which is affected to a great extent by exogenous CoQ10. It has long been known
that after a single or prolonged administration of CoQ10 small increases can be found in heart, muscle and other organs while remarkably high amounts of CoQ10 can be found in liver and plasma and high ubiquinol concentrations in plasma certainly protect the arteries.
1. Digiesi V, Cantini F, Oradei A, Bisi G, Guarino GC, Brocchi A, Bellandi F, Mancini M, Littarru GP. Coenzyme Q10 in essential hypertension. Mol Aspects Med. 1994;15 Suppl:s257-‐63.
2. Stocker R, Bowry VW, Frei B. Ubiquinol-‐10 protects human low density lipoprotein more efficiently against lipid peroxidation than does alpha-‐tocopherol. Proc Natl Acad Sci U S A. 1991 Mar 1;88(5):1646-‐50.
3. Littarru GP, Tiano L, Belardinelli R, Watts GF. Coenzyme Q(10) , endothelial function, and cardiovascular disease. Biofactors. 2011 Sep-‐Oct;37(5):366-‐73.
4. Brugè F, Bacchetti T, Principi F, Scarpa ES, Littarru GP, Tiano L. Olive oil supplemented with Coenzyme Q(10): effect on plasma and lipoprotein oxidative status. Biofactors. 2012 May-‐Jun;38(3):249-‐56.
5. Watts GF, Playford DA, Croft KD, Ward NC, Mori TA, Burke V. Coenzyme Q(10) improves endothelial dysfunction of the brachial artery in Type II diabetes mellitus. Diabetologia. 2002 Mar;45(3):420-‐6.
6. Belardinelli R, Mucaj A, Lacalaprice F, Solenghi M, Seddaiu G, Principi F,Tiano L, Littarru GP. Coenzyme Q10 and exercise training in chronic heart failure. Eur Heart J. 2006 Nov;27(22):2675-‐81.
7. Tiano L, Belardinelli R, Carnevali P, Principi F, Seddaiu G, Littarru GP. Effect of coenzyme Q10 administration on endothelial function and extracellular superoxide dismutase in patients with ischaemic heart disease: a double-‐blind, randomized controlled study. Eur Heart J. 2007 Sep;28(18):2249-‐55.
8. Alehagen U, Johansson P, Bjornstedt M, Rosen A, Dahlstrom U. Cardiovascular mortality and N-‐terminal-‐proBNP reduced after combined selenium and coenzyme Q10 supplementation: a 5-‐year prospective randomized double-‐blind placebo-‐controlled trial among elderly Swedish citizens. Int J Cardiol. 2013 Sep 1;167(5):1860-‐6.
9. Olivieri Anti-‐inflammatory effect of ubiquinol-‐10 on young and senescent endothelial cells via miR-‐146a modulation. Olivieri F, Lazzarini R, Babini L, Prattichizzo F, Rippo MR, Tiano L, Di Nuzzo S, Graciotti L, Festa R, Brugè F, Orlando P, Silvestri S, Capri M, Palma L, Magnani M, Franceschi C, Littarru GP, Procopio AD. Free Radic Biol Med. 2013
Oct;63:410-‐20. doi: 10.1016/j.freeradbiomed.2013.05.033. Epub 2013 May 30.