Enhance Endothelial Health
How Pomegranate Protects Against AtherosclerosisNovember 2014
By James Harrison
Human Studies Support Pomegranate
Pomegranate’s ability to mobilize the body’s own self-defense forces against endothelial dysfunction are validated by human studies. A dose of 150 mL of fresh pomegranate juice once daily for two weeks in patients with hypertension demonstrated reductions in both systolic (top number) and diastolic (bottom number) blood pressures. These changes were accompanied by significant decreases in levels of vascular cell adhesion molecule-1 (VCAM-1), an important endothelial-produced inflammatory protein.8,34 These changes after such a short period indicate the potential for long-term benefit of pomegranate supplementation on blood pressure and the inflammation that raises risk for heart attack and stroke.8
One common way of determining endothelial function and early atherosclerosis risk is to measure the thickness of inner and middle layers of the arterial wall, where the endothelium and muscle layers lie, respectively.35 This measure, called intima-media thickness (IMT) after the names of those layers, is an excellent predictor of future cardiovascular events.36 Increased IMT is associated with vascular risk factors and cardiovascular diseases.36
In a study of pomegranate juice supplementation in a group of people who already had increased IMT, the results showed those who did not consume the pomegranate had a 9% increase in IMT over one year. Those who did drink pomegranate juice had an average reduction in IMT of up to 30%.9 This was accompanied by an 83% increase in the patients’ levels of the beneficial antioxidant enzyme PON-1. Additionally, levels of oxidized LDL dropped by 90%, further reducing risk of heart attack or stroke, probably related to the fact that total antioxidant status was increased by 130% after a year of pomegranate supplementation. These beneficial changes were accompanied by a 12% reduction in systolic blood pressure over one year.9
A subsequent study revealed that pomegranate supplementation also reduced progression of IMT thickening in those subjects with the worst oxidative stress and highest triglyceride/lowest HDL groups.10 These studies provide direct evidence of how pomegranate ramps up the body’s protective responses to reduce the risk of cardiovascular disease.
In a remarkable 2014 study, researchers found that adding pomegranate extract to the cholesterol-lowering drug simvastatin lowered dangerous production of reactive oxygen species in white blood cells from patients with high cholesterol by 30%, compared with only an 18% decrease in those on the drug only.37 Similarly, the pomegranate-plus-simvastatin group saw a significant 48% reduction in triglyceride levels, which did not fall in the drug-only group.37
Pomegranate seed oil contains punicic acid, a beneficial fatty acid unique to pomegranate. Lab studies have shown it to have powerful anti-atherogenic effects.38 A human study demonstrated that after four weeks of pomegranate seed oil, 400 mg twice daily in people with high cholesterol, their triglyceride levels fell from 306 mg/dL to 244 mg/dL, and their ratios of triglyceride to HDL cholesterol (an important measure of cardiovascular risk) fell from 7.5 to a safer 5.7. Supplemented patients also had a beneficial increase of 5 mg/dL in HDL-cholesterol, which fell by 0.77 mg/dL in placebo recipients.38
Editor’s note: Triglyceride levels should optimally be below 100 mg/dL. Fish oil and the prescription drug metformin can sharpy lower triglyceride levels.
Your endothelium, the thin layer of cells lining your blood vessels, is the major regulator of blood flow and pressure, communicating with the smooth muscle cells via signaling molecules including nitric oxide.
Aging increases oxidant stresses that destroy nitric oxide, while simultaneously reducing protective antioxidant mechanisms. This leads to atherosclerosis, formerly known as “hardening of the arteries,” which in turn, is the major cause of heart attack and stroke.
Pomegranate extracts act via several different, but complementary mechanisms to restore the body’s endothelial defenses, lowering risk factors for a cardiovascular event, and helping to keep arteries supple and youthful. Pomegranate extracts have been shown to promote cholesterol outflow from macrophages, to enhance natural antioxidant systems like superoxide dismutase (SOD), and to directly protect LDL from oxidant damage and resulting inflammation.
A robust form of the antioxidant enzyme SOD has been developed that enhances SOD activity beyond what is provided by pomegranate. Studies show that this product, GliSODin®, survives passage through the stomach to boost SOD levels, which may reduce cardiovascular risk by improving endothelial health.48
If you have any questions on the scientific content of this article, please call a Life Extension® Health Advisor at 1-866-864-3027.
- Gawryszewski VP, Souza Mde F. Mortality due to cardiovascular diseases in the Americas by region, 2000-2009. Sao Paulo Med J. 2014;132(2):105-10.
- Kelly BB, Narula J, Fuster V. Recognizing global burden of cardiovascular disease and related chronic diseases. Mt Sinai J Med. 2012 Nov-Dec;79(6):632-40.
- Houston M. The role of nutrition and nutraceutical supplements in the treatment of hypertension. World J Cardiol. 2014 Feb 26;6(2):38-66.
- Stoltz JF, Muller S, Kadi A, Decot V, Menu P, Bensoussan D. Introduction to endothelial cell biology. Clin Hemorheol Microcirc. 2007;37(1-2):5-8.
- Kaplan M, Hayek T, Raz A, et al. Pomegranate juice supplementation to atherosclerotic mice reduces macrophage lipid peroxidation, cellular cholesterol accumulation and development of atherosclerosis. J Nutr. 2001 Aug;131(8):2082-9.
- Rosenblat M, Volkova N, Aviram M. Pomegranate juice (PJ) consumption antioxidative properties on mouse macrophages, but not PJ beneficial effects on macrophage cholesterol and triglyceride metabolism, are mediated via PJ-induced stimulation of macrophage PON2. Atherosclerosis. 2010 Sep;212(1):86-92.
- Aviram M, Rosenblat M. Pomegranate for your cardiovascular health. Rambam Maimonides Med J. 2013 Apr;4(2):e0013.
- Asgary S, Sahebkar A, Afshani MR, Keshvari M, Haghjooyjavanmard S, Rafieian-Kopaei M. Clinical evaluation of blood pressure lowering, endothelial function improving, hypolipidemic and anti-Inflammatory effects of pomegranate juice in hypertensive subjects. Phytother Res. 2014 Feb;28)2)193-9.
- Aviram M, Rosenblat M, Gaitini D, et al. Pomegranate juice consumption for 3 years by patients with carotid artery stenosis reduces common carotid intima-media thickness, blood pressure and LDL oxidation. Clin Nutr. 2004 Jun;23(3):423-33.
- Davidson MH, Maki KC, Dicklin MR, et al. Effects of consumption of pomegranate juice on carotid intima-media thickness in men and women at moderate risk for coronary heart disease. Am J Cardiol. 2009 Oct 1;104(7):936-42.
- Puddu GM, Cravero E, Arnone G, Muscari A, Puddu P. Molecular aspects of atherogenesis: new insights and unsolved questions. J Biomed Sci. 2005 Dec;12(6):839-53.
- Lee WJ, Ou HC, Hsu WC, et al. Ellagic acid inhibits oxidized LDL-mediated LOX-1 expression, ROS generation, and inflammation in human endothelial cells. J Vasc Surg. 2010 Nov;52(5):1290-300.
- Seals DR, Jablonski KL, Donato AJ. Aging and vascular endothelial function in humans. Clin Sci (London). 2011 May;120(9):357-75.
- Karbach S, Wenzel P, Waisman A, Munzel T, Daiber A. eNOS uncoupling in cardiovascular diseases - the role of oxidative stress and inflammation. Curr Pharm Des. 2014;20(22)3579-94.
- Ide N, Lau BH. Garlic compounds protect vascular endothelial cells from oxidized low density lipoprotein-induced injury. J Pharm Pharmacol. 1997 Sep;49(9):908-11.
- Sirtori CR. The pharmacology of Statins. Pharmacol Res. 2014 Mar 20. Pii:S1043- 66618(14)00025-5.
- Reilly SD, Litovsky SH, Steinkampf MP, Caulfield JB. Statins improve human coronary atherosclerotic plaque morphology. Tex Heart Inst J. 2008;35(2):99-103.
- Cosentino F, Rubattu S, Savoia C, Venturelli V, Pagannonne E, Volpe M . Endothelial dysfunction and stroke. J Cardiovasc Pharmacol. 2001 Nov;38 Suppl 2:S75-8.
- Yin K, Liao DF, Tang CK. ATP-binding membrane cassette transporter A1 (ABCA1): a possible link between inflammation and reverse cholesterol transport. Mol Med. 2010;16(9-10):438-49.
- Lobo V, Patil A, Phatak A, Chandra N. Free radicals, antioxidants and functional foods: Impact on human health. Pharmacogn Rev. 2010 Jul;4(8):118-26.
- Cuchel M, Rader DJ. Macrophage reverse cholesterol transport: key to the regression of atherosclerosis? Circulation. 2006 May 30;113(21):2548-55.
- Vohl MC, Neville TA, Kumarathasan R, Braschi S, Sparks DL. A novel lecithin-cholesterol acyltransferase antioxidant activity prevents the formation of oxidized lipids during lipoprotein oxidation. Biochemistry . 1999 May 11;38(19):5976-81.
- Holleboom AG, Daniil G, Fu X, et al. Lipid oxidation in carriers of lecithin:cholesterol acyltransferase gene mutations. Arterioscler Thromb Vasc Biol. 2012 Dec;32(12):3066-75.
- Goyal J, Wang K, Liu M, Subbaiah PV. Novel function of lecithin--terol acyltransferase. Hydrolysis of oxidized polar phospholipids generated during lipoprotein oxidation. J Biol Chem. 1997;272:16231–9.
- Fuhrman B, Volkova N, Aviram M. Pomegranate juice inhibits oxidized LDL uptake and cholesterol biosynthesis in macrophages. J Nutr Biochem. 2005 Sep;16(9):570-6.
- Dong S, Tong X, Liu H, Gao Q. Protective effects of pomegranate polyphenols on cardiac function in rats with myocardial ischemia/reperfusion injury. Nan Fang Yi Ke Da Xue Xue Bao. 2012 Jun;32(7):924-7.
- Mohan M, Waghulde H, Kasture S. Effect of pomegranate juice on Angiotensin II-induced hypertension in diabetic Wistar rats. Phytother Res. 2010 Jun;24 Suppl 2:S196-203.
- Shaban NZ, El-Kersh MA, El-Rashidy FH, Habashy NH. Protective role of Punica granatum (pomegranate) peel and seed oil extracts on diethylnitrosamine and phenobarbital-induced hepatic injury in male rats. Food Chem. 2013 Dec 1;141(3):1587-96.
- Aviram M, Rosenblat M. Pomegranate protection against cardiovascular diseases. Evid Based Complement Alternat Med. 2012;2012:382763.
- Al-Jarallah A, Igdoura F, Zhang Y, et al. The effect of pomegranate extract on coronary artery atherosclerosis in SR-BI/APOE double knockout mice. Atherosclerosis. 2013 May;228(1):80-9.
- Hassanpour Fard M, Ghule AE, Bodhankar SL, Dikshit M. Cardioprotective effect of whole fruit extract of pomegranate on doxorubicin-induced toxicity in rat. Pharm Biol. 2011 Apr;49(4):377-82.
- Zhou S, Palmeira CM, Wallace KB. Doxorubicin-induced persistent oxidative stress to cardiac myocytes. Toxicol Lett. 2001 May 19;121(3):151-7.
- Rosenblat M, Volkova N, Aviram M. Addition of pomegranate juice to statin inhibits cholesterol accumulation in macrophages: protective role for the phytosterol beta-sitosterol and for the polyphenolic antioxidant punicalagin. Harefuah. 2013 Sep;152(9):513-5, 565.
- Cook-Mills JM, Marchese ME, Abdala-Valencia H. Vascular cell adhesion molecule-1 expression and signaling during disease: regulation by reactive oxygen species and antioxidants. Antioxid Redox Signal. 2011 Sep 15;15(6):1607-38.
- Sobieszczyk P, Beckman J. Carotid artery disease. Circulation. 2006 Aug 15;114(7):e244-7.
- Lorenz MW, Markus HS, Bots ML, Rosvall M, Sitzer M. Prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysis. Circulation. 2007 Jan 30;115(4):459-67.
- Hamoud S, Hayek T, Volkova N, et al. Pomegranate extract (POMx) decreases the atherogenicity of serum and of human monocyte-derived macrophages (HMDM) in simvastatin-treated hypercholesterolemic patients: A double-blinded, placebo-controlled, randomized, prospective pilot study. Atherosclerosis. 2014 Jan;232(1):204-10.
- Mirmiran P, Fazeli MR, Asghari G, Shafiee A, Azizi F. Effect of pomegranate seed oil on hyperlipidaemic subjects: a double-blind placebo-controlled clinical trial. Br J Nutr. 2010 Aug;104(3):402-6.
- Chang MS, Lee SG, Rho HM. Transcriptional activation of Cu/Zn superoxide dismutase and catalase genes by panaxadiol ginsenosides extracted from Panax ginseng. Phytother Res. 1999 Dec;13(8):641-4.
- Marklund SL. Extracellular superoxide dismutase in human tissues and human cell lines. J Clin Invest. 1984 Oct;74(4):1398-403.
- Marklund SL. Extracellular superoxide dismutase and other superoxide dismutase isoenzymes in tissues from nine mammalian species. Biochem J. 1984 Sep 15;222(3):649-55.
- Afonso V, Champy R, Mitrovic D, Collin P, Lomri A. Reactive oxygen species and superoxide dismutases: role in joint diseases. Joint Bone Spine. 2007 Jul;74(4):324-9.
- Edsmyr F, Menander-Huber KB. Orgotein efficacy in ameliorating side effects due to radiation therapy. Eur J Rheumatol Inflamm. 1981;4(2):228-36.
- Esco R, Valencia J, Coronel P, Carceller JA, Gimeno M, Bascon N. Efficacy of orgotein in prevention of late side effects of pelvic irradiation: a randomized study. Int J Radiat Oncol Biol Phys. 2004 Nov 15;60(4):1211-9.
- Gammer W, Broback LG. Clinical comparison of orgotein and methylprednisolone acetate in the treatment of osteoarthrosis of the knee joint. Scand J Rheumatol. 1984;13(2):108-12.
- Lin Y, Pape HD, Friedrich R. Use of superoxide dismutase (SOD) in patients with temporomandibular joint dysfunction--a preliminary study. Int J Oral Maxillofac Surg. 1994 Dec;23(6 Pt 2):428-9.
- Mazieres B, Masquelier AM, Capron MH. A French controlled multicenter study of intraarticular orgotein versus intraarticular corticosteroids in the treatment of knee osteoarthritis: a one-year followup. J Rheumatol Suppl. 1991 Feb;27:134-7.
- Vouldoukis I, Conti M, Krauss P, et al. Supplementation with gliadin-combined plant superoxide dismutase extract promotes antioxidant defences and protects against oxidative stress. Phytother Res. 2004 Dec;18(12):957-62.
- Cloarec M, Caillard P, Provost JC, Dever JM, Elbeze Y, Zamaria N. GliSODin, a vegetal sod with gliadin, as preventative agent vs. atherosclerosis, as confirmed with carotid ultrasound-B imaging. Eur Ann Allergy Clin Immunol. 2007 Feb;39(2):45-50.
- Skarpanska-Stejnborn A, Pilaczynska-Szczesniak L, Basta P, Deskur-Smielecka E, Woitas-Slubowska D, Adach Z. Effects of oral supplementation with plant superoxide dismutase extract on selected redox parameters and an inflammatory marker in a 2,000-m rowing-ergometer test. Int J Sport Nutr Exerc Metab. 2011 Apr;21(2):124-34.
- Nakajima S, Ohsawa I, Nagata K, et al. Oral supplementation with melon superoxide dismutase extract promotes antioxidant defences in the brain and prevents stress-induced impairment of spatial memory. Behav Brain Res. 2009 Jun 8;200(1):15-21.
- Okumachi Y, Yokono K. Anti-aging medicine: the evidence to the value of the antihypertensive drugs, hypoglycemic drugs and statins. Nippon Rinsho. 2009 Jul;67(7):1372-6.
- Kekes E. Combined antihypertensive and antilipemic therapy as one of the pillars in the poly-pharmacologic preventive strategy for patients with high cardiovascular risk. Orv Hetil. 2008 Sep 28;149(39):1827-37.
- Gouedard C, Koum-Besson N, Barouki R, Morel Y. Opposite regulation of the human paraoxonase-1 gene PON-1 by fenofibrate and statins. Mol Pharmacol . 2003 Apr;63(4):945-56.
- Rozenberg O, Rosenblat M, Coleman R, Shih DM, Aviram M. Paraoxonase (PON-1) deficiency is associated with increased macrophage oxidative stress: studies in PON-1-knockout mice. Free Radic Biol Med. 2003 Mar 15;34(6):774-84.
- Leus FR, Wittekoek ME, Prins J, Kastelein JJ, Voorbij HA. Paraoxonase gene polymorphisms are associated with carotid arterial wall thickness in subjects with familial hypercholesterolemia. Atherosclerosis. 2000 Apr;149(2):371-7.
- Watson AD, Berliner JA, Hama SY, et al. Protective effect of high density lipoprotein associated paraoxonase. Inhibition of the biological activity of minimally oxidized low density lipoprotein. J Clin Invest. 1995 Dec;96(6):2882-91.
- Ikeda Y, Suehiro T, Itahara T, et al. Human serum paraoxonase concentration predicts cardiovascular mortality in hemodialysis patients. Clin Nephrol. 2007 Jun;67(6):358-65.