Pomegranate and Cardiovascular Dseases

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Adv Biomed Res. 2014 Mar 25;3:100. doi: 10.4103/2277-9175.129371

Potent health effects of pomegranate

Aida Zarfeshany 1, Sedigheh Asgary 1,✉, Shaghayegh Haghjoo Javanmar

Cardiovascular diseases

Pomegranate juice is an affluent source of polyphenols with high antioxidative potential. Moreover, its antiatherogenic, antihypertensive, and anti-inflammatory effects have been shown in limited studies in human and murine models.[15]Hypertension is the most common disease in primary care of patients. It is found in comorbidity with diabetes and cardiovascular disease, and the majority of patients do not tend to be medicated. Pomegranate juice prevents the activity of serum angiotensin-converting enzyme and reduces systolic blood pressure.[16] Angiotensin II acute subcutaneous administration causes increased blood pressure in diabetic Wistar rats. It has been shown that pomegranate juice administration (100 mg/kg) for 4 weeks could reduce the mean arterial blood pressure.[17] Pomegranate juice consumption resulted in 30% decrease in carotid intima-media thickness after 1 year. The patient's serum paraoxonase 1 (PON 1) activity showed 83% increase, whereas both serum low dwnsity lipoprotein (LDL) basal oxidative state and LDL susceptibility to copper ion significantly decreased by 90% and 95%, respectively.[18]

In cultured human endothelial cells and hypercholesterolemic mice, both pomegranate juice and fruit extract reduced the activation of ELK-1 and p-CREB (oxidation-sensitive responsive genes) and elevated the expression of endothelial nitric oxide synthase. It is suggested that polyphenolic antioxidant compounds in pomegranate juice are responsible for the reduction of oxidative stress and atherogenesis.[22

Punicic acid, which is the main constituent of pomegranate seed oil, has antiatherogenic effects. In a study on 51 hyperlipidemic patients, pomegranate seed oil was administered twice a day (800 mg/day) for 4 weeks. There was a significant decrease in triglycerides (TG) and TG: High density lipoprotein (HDL) cholesterol ratio by 2.75 mmol/L and 5.7 mmol/L, respectively, whereas serum cholesterol, LDL-C, and glucose concentration remained unchanged.[19]

High plasma LDL concentration is the major risk factor for atherosclerosis. Therefore, LDL modifications, including oxidation, retention, and aggregation, play a key role in atherosclerosis as well. Studies have shown that consuming pomegranate juice for 2 weeks resulted in declined retention and aggregation of LDL susceptibility and increased activity of serum paraoxonase (a protective lipid peroxidation esterase related to HDL) by 20% in humans. Pomegranate juice administration in mice for 14 weeks showed reduced LDL oxidation by peritoneal macrophages by more than 90%, which was because of reduced cellular lipid peroxidation and superoxide release. The uptake of oxidized LDL showed 20% reduction in mice. The size of atherosclerotic lesions reduced by 44% after pomegranate juice supplementation.[20] Moreover, pomegranate juice administration to apolipoprotein E-deficient mice with advanced atherosclerosis for 2 months reduced oxidized LDL (31%) and increased macrophage cholesterol efflux (39%).[21]

In cultured human endothelial cells and hypercholesterolemic mice, both pomegranate juice and fruit extract reduced the activation of ELK-1 and p-CREB (oxidation-sensitive responsive genes) and elevated the expression of endothelial nitric oxide synthase. It is suggested that polyphenolic antioxidant compounds in pomegranate juice are responsible for the reduction of oxidative stress and atherogenesis.[22

 another study,[23] concentrated pomegranate juice was shown to reduce heart disease risk factors. Administration of concentrated pomegranate juice to 22 diabetic type 2 patients with hyperlipidemia could significantly reduce TC, LDL-C, LDL-C: HDL-C ratio, and TC: HDL-C ratio. However, it was unable to decrease serum TG and HDL-C concentrations.

Oral administration of pomegranate flower aqueous extract in streptozotocin (STZ)-induced albino Wistar rats in both 250 mg/kg and 500 mg/kg doses for 21 days could significantly reduce fibrinogen (FBG), TC, TG, LDL-C, and tissue lipid peroxidation level and increased the level of HDL-C and glutathione content.[24]

Heart fibrosis increases among diabetics, which results in impairing cardiac function. Endothelin (ET)-1 and NFκB are interactive fibroblast growth regulators. It is suggested that pomegranate flower extract (500 mg/kg/day) in Zucker diabetic fatty rats could reduce the ratios of van Gieson-stained interstitial collagen deposit area to a total left ventricular area and perivascular collagen deposit areas to coronary artery media area in the heart and diminishes cardiac fibrosis in these rats. In addition, overexpressed cardiac fibronectin and collagen I and II messenger RNAs (mRNAs) were inhibited. It also decreased the upregulated cardiac mRNA expression of ET-1, ETA, inhibitor-κBβ, and c-jun. Pomegranate flower extract is a dual activator of peroxisome proliferator-activated receptor (PPAR)-α and γ and improves hyperlipidemia, hyperglycemia, and fatty heart in diabetic fatty Zucker rats.[25,26]

Punicic acid caused a dose-dependent increase in PPAR alpha and gamma reporter activity in 3T3-L1 cells. Dietary punicic acid reduced plasma glucose, suppressed NFκB activation and unregulated TNF-α expression and PPAR-α/γ responsive genes in adipose tissue and skeletal muscle.[27]

Pomegranate leaf extract was administered (400 and 800 mg/kg/day) to high-fat-diet-induced obese and hyperlipidemic mouse models for 5 weeks. The results indicated significant reduction in body weight, energy intake (based on food intake), serum total cholesterol (TC), TG, FBG, and TC/HDL-C ratio. Intestinal fat absorption was inhibited as well.[28]

The high fat diet (HFD) with 1% pomegranate seed oil (rich source of punicic acid) was administered for 12 weeks to induce obesity and insulin resistance in mice. The pomegranate seed oil-fed group exhibited lower body weight (4%) and body fat mass (3.1%) compared with only HFD-fed mice. A clear improvement was observed in peripheral insulin sensitivity (70%) in pomegranate seed oil-administered rats.[29]

Fatty liver is the most common abnormal liver function among diabetics. Pomegranate flower was examined for its antidiabetic effects on diabetic type II and obese Zucker rats. Rats fed with 500 mg/kg/day of pomegranate flower extract for 6 weeks showed decreased ratio of liver weight to tibia length, lipid droplets, and hepatic TG contents. In addition, it increased PPRA-α and Acyl-COA oxidase mRNA levels in HepG2 cells.[30]

In a study by de Nigris et al.,[31] they compared the influence of pomegranate fruit extract with pomegranate juice on nitric oxide and arterial function in obese Zucker rats. They have demonstrated that both pomegranate fruit extract and juice significantly reduced the vascular inflammatory markers expression, thrombospondin, and cytokine TGFP 1. Increased plasma nitrite and nitrate were observed with administration of either pomegranate fruit or juice.

Many studies have reported the anti-inflammatory potential of pomegranate extract. In a study on 30 Sprague-Dawley rats with acute inflammation due to myringotomy, it was observed that 100 μl/day of pomegranate extract could significantly reduce reactive-oxygen species (ROS) levels. The extract was administered 1 day before and 2 days after surgery. Reduced thickness of lamina propria and vessel density was reported as well.[32] Both ellagitannins and ellagic acid are the main components of pomegranate extract, which have anti-inflammatory properties. They are metabolized by gut microbiota to yield urolithins. It is suggested that urolithins are the main components responsible for the anti-inflammation properties of pomegranate. It is suggested that NFκB activation, MAPK downregulation of COX-2, and mPGES-1 expression were inhibited through a decrease in PGE2 production.[33] Neutrophils play key roles in inflammatory processes by releasing great amounts of ROS generated by NADPH-oxidase and myeloperoxidase. It is indicated that punicic acid exhibited a potent anti-inflammatory effect via prevention of TNF-α-induced priming of NADPH oxidase by targeting the p38MAPKinase/Ser 345-p 47 phox-axis and releasing MPO.[34] Hyperglycemia results in oxidative stress in diabetes mellitus, which is a major factor in the pathogenesis of cardiovascular disease. Results suggested that pomegranate extract, owing to its polyphenol-rich antioxidants (oleanolic, ursolic, and gallic acids), could prevent cardiovascular complications through decrease in LDL, increase in HDL, serum paraoxonase 1 stability and activity, and nitric oxide production.[35,36,37]