CARDIOVASCULAR ABSTRACTS CONTINUED

CARDIOVASCULAR --- CURCUMIN

1: Biochem Pharmacol. 2007 Aug 19;
Curcumin as "Curecumin": From kitchen to clinic.
Goel A, Kunnumakkara AB, Aggarwal BB.
Gastrointestinal Cancer Research Laboratory, Department of Internal Medicine, Charles A. Sammons Cancer Center and Baylor Research Institute, Baylor University Medical Center, Dallas, TX, United States.

Although turmeric (Curcuma longa; an Indian spice) has been described in Ayurveda, as a treatment for inflammatory diseases and is referred by different names in different cultures, the active principle called curcumin or diferuloylmethane, a yellow pigment present in turmeric (curry powder) has been shown to exhibit numerous activities. Extensive research over the last half century has revealed several important functions of curcumin. It binds to a variety of proteins and inhibits the activity of various kinases. By modulating the activation of various transcription factors, curcumin regulates the expression of inflammatory enzymes, cytokines, adhesion molecules, and cell survival proteins. Curcumin also downregulates cyclin D1, cyclin E and MDM2; and upregulates p21, p27, and p53. Various preclinical cell culture and animal studies suggest that curcumin has potential as an antiproliferative, anti-invasive, and antiangiogenic agent; as a mediator of chemoresistance and radioresistance; as a chemopreventive agent; and as a therapeutic agent in wound healing, diabetes, Alzheimer disease, Parkinson disease, cardiovascular disease, pulmonary disease, and arthritis. Pilot phase I clinical trials have shown curcumin to be safe even when consumed at a daily dose of 12g for 3 months. Other clinical trials suggest a potential therapeutic role for curcumin in diseases such as familial adenomatous polyposis, inflammatory bowel disease, ulcerative colitis, colon cancer, pancreatic cancer, hypercholesteremia, atherosclerosis, pancreatitis, psoriasis, chronic anterior uveitis and arthritis. Thus, curcumin, a spice once relegated to the kitchen shelf, has moved into the clinic and may prove to be "Curecumin".

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Adv Exp Med Biol. 2007;595:359-77.
Cardioprotective effects of curcumin.
Miriyala S, Panchatcharam M, Rengarajulu P.
Department of Medicine, Carolina Cardiovascular Biology Center, University of North Carolina, Chapel Hill 27599, USA. sumishree@hotmail.com

Curcumin, a major active component of turmeric, is extracted from the powdered dry rhizome of Curcuma longa Linn (Zingiberaceae) and it has been used for centuries in indigenous medicine. We have shown that curcumin has a protective role against myocardial necrosis in rats. The antioxidant activity of curcumin could be attributed to the phenolic and methoxy groups in conjunction with the 1,3-diketone-conjugated diene system, for scavenging of the oxygen radicals. In addition, curcumin is shown to enhance the activities of detoxifying enzymes such as glutathione-S-transferase in vivo. We have also shown that oxygen free radicals exacerbate cardiac damage and curcumin induces cardioprotective effect and it also inhibits free-radical generation in myocardial ischemia in rats. This chapter on the cardioprotective effects of curcumin covers the following aspects: (1) the history of curcumin and its discovery as a potent drug with relevance to cardiovascular diseases; (2) mechanistic role of curcumin in vitro, emphasizing the antiplatelet and anticoagulant effects; (3) cardiovascular properties of curcumin; (4) application of curcumin in different animal models (viz. myocardial ischemia, myocardial infarction, cardiomyopathy, and arrhythmia in vitro and in vivo); (5) curcumin free-radical scavenging activity, particularly against O2 radical and depletion of the oxidative stress.

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Vascul Pharmacol. 2007 Jul;47(1):25-30. Epub 2007 Mar 27
THE RELAXANT EFFECT OF CURCUMIN ON THE P0RCINE CORNARY ARTERIAL RING SEGMENTS.
Xu PH, Long Y, Dai F, Liu ZL.
National Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, Gansu 730000, China. xupeihan2005@yahoo.com.cn

Curcumin is a naturally occurring phenolic compound isolated as a yellow pigment from turmeric (curcuma longa). This compound has received much attention due to its diversity of biological and pharmacological activities. The purpose of this study was to assess the effect of curcumin on porcine coronary arteries and to investigate the mechanism of its action, if any. The isometric tension of coronary arterial rings taken from porcine hearts was measured and its response to curcumin (10(-11)-10(-5) mol/l) was studied. It was found that curcumin significantly reduced the isomeric tension of both quiescent and prostaglandin F2alpha (PGF2alpha) precontracted porcine coronary arterial rings. The relaxing effect of curcumin on coronary arteries was significantly reduced by removal of endothelium, and by the addition of N-nitro-L-arginine (L-NNA), methylene blue or propranolol, but not by indomethacin. These results suggest that curcumin-induced relaxation of isolated porcine coronary arteries might involve the action of nitric oxide (NO), cyclic guanosine monophosphate (cGMP) and adrenergic beta-receptor, but not involve the synthesis of prostaglandin.

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J Physiol Pharmacol. 2005 Dec;56(4):627-35
Effect of curcumin on atherosclerosis in apoE/LDLR-double knockout mice.
Olszanecki R, Jawień J, Gajda M, Mateuszuk L, Gebska A, Korabiowska M, Chłopicki S, Korbut R.
Department of Histology, Jagiellonian University School of Medicine, Cracow, Poland. mfolszan@cyf-kr.edu.pl

It is widely appreciated that inflammation and oxidant stress contribute to atherogenesis. Curcumin, a polyphenolic natural compound has been reported to possess anti-inflammatory and anti-oxidant actions. We hypothesized that curcumin could inhibit the development of atherosclerosis in the apoE/LDLR-double knockout mice fed with Western diet (21% fat, 0.15% cholesterol w/w, without cholic acid). Curcumin (purity>or=98%), premixed with diet, was given for 4 months at a dose of 0.3 mg/ per day/ per mouse. In this model curcumin inhibited atherogenesis, measured both by "en face" method (25,15+/-2,9% vs. 19,2+/-0,6%, p<0,05) and "cross-section" method (565867+/-39764 microm2 vs. 299201+/-20373 microm2, p<0,05). Importantly, curcumin influenced neither the concentrations of cholesterol and triglycerides in blood nor animal body weight. To our knowledge, this is the first report that shows the anti-atherogenic effect of low dose of curcumin in fine model of atherosclerosis: gene-targeted apoE/LDLR-double knockout mice.

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Ann N Y Acad Sci. 2005 Nov;1056:206-17.
Curcumin: getting back to the roots.
Shishodia S, Sethi G, Aggarwal BB.
Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.

The use of turmeric, derived from the root of the plant Curcuma longa, for treatment of different inflammatory diseases has been described in Ayurveda and in traditional Chinese medicine for thousands of years. The active component of turmeric responsible for this activity, curcumin, was identified almost two centuries ago. Modern science has revealed that curcumin mediates its effects by modulation of several important molecular targets, including transcription factors (e.g., NF-kappaB, AP-1, Egr-1, beta-catenin, and PPAR-gamma), enzymes (e.g., COX2, 5-LOX, iNOS, and hemeoxygenase-1), cell cycle proteins (e.g., cyclin D1 and p21), cytokines (e.g., TNF, IL-1, IL-6, and chemokines), receptors (e.g., EGFR and HER2), and cell surface adhesion molecules. Because it can modulate the expression of these targets, curcumin is now being used to treat cancer, arthritis, diabetes, Crohn's disease, cardiovascular diseases, osteoporosis, Alzheimer's disease, psoriasis, and other pathologies. Interestingly, 6-gingerol, a natural analog of curcumin derived from the root of ginger (Zingiber officinalis), exhibits a biologic activity profile similar to that of curcumin. The efficacy, pharmacologic safety, and cost effectiveness of curcuminoids prompt us to "get back to our roots."

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CARDIOVASCULAR --- BROMELAIN

In Vivo. 1999 Jan-Feb;13(1):7-12
Bromelain proteases reduce human platelet aggregation in vitro, adhesion to bovine endothelial cells and thrombus formation in rat vessels in vivo.
Metzig C, Grabowska E, Eckert K, Rehse K, Maurer HR.
Institute of Pharmacy, Free University of Berlin, Germany.

The thiol protease, bromelain, an extract from pineapple stem, was suggested to have antithrombotic and anticoagulant activities in vivo. We studied the effects of bromelain on cell size distribution of isolated human platelets in vitro by Coulter Counter measurements. Preincubation of platelets with bromelain (10 micrograms/mL) completely prevented the thrombin (0.2 U/mL) induced platelet aggregation. Papain was less active in preventing platelet aggregation. In vitro, bromelain (0.1 microgram/mL) reduced the adhesion of bound, thrombin stimulated, fluorescent labeled platelets to bovine aorta endothelial cells. In addition, preincubation of platelets with bromelain, prior to thrombin, activation, reduced the platelet adhesion to the endothelial cells to the low binding value of unstimulated platelets. On the basis of mass concentrations, the proteases papain and trypsin were as effective as bromelain. Using a laser thrombosis model, the in vivo effects of orally and intraveneously applied bromelain on thrombus formation in rat mesenteric vessels were studied. Bromelain, orally applied at 60 mg/kg body weight, inhibited the thrombus formation in a time dependent manner, the maximum being after 2 hours in 11% of arterioles and 6% of venoles. Intravenous application at 30 mg/kg was slightly more active in reducing thrombus formation in arterioles (13%) and venoles (5%), suggesting that orally applied bromelain is biologically active. These results may help to explain some of the clinical effects observed after bromelain treatment in patients with thrombosis and related diseases.

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CARDIOVASCULAR --- QUERCETIN

Basic Clin Pharmacol Toxicol. 2007 Sep;101(3):197-202
Protective Effect of Quercetin on the Homocysteine-Injured Human Umbilical Vein Vascular Endothelial Cell Line (ECV304).
Lin R, Liu J, Gan W, Ding C.
Department of Pharmacology, School of Medicine, Xi’an Jiaotong University, Xi’an, Shaanxi, and Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, Shaanxi, China.

Homocysteine is responsible for the occurrence of many cardiovascular diseases for instance by injuring the vascular endothelial cells. Quercetin has many beneficial effects on the cardiovascular system, but it is unknown whether it provides protection against homocysteine-injured vascular endothelial cells. The aim of the present study was to investigate the protective effect and mechanism of quercetin on the homocysteine-injured human umbilical vein vascular endothelial cell line (ECV304) (i.e. morphology, viability and nuclear factor kappa B (NF-kappaB) expression of ECV304 injured with 1.0 mM homocysteine) by determination of lipid peroxidant and endothelium-derived factors in the cultural medium of homocysteine-injured ECV304. Quercetin at 6.25, 12.5, 25, 50 and 100 microM attenuated the morphological changes and increased viability of homocysteine-injured ECV304 in a dose-dependent manner (P < 0.05 or P < 0.01 versus the homocysteine-injured group). At the same time, quercetin at 12.5, 25 and 50 microM decreased malondialdehyde level, endothelin release and NF-kappaB expression, and increased superoxide dismutase activity, nitric oxide and 6-keto-prostaglandin F1alpha releases in homocysteine-injured ECV304 (P < 0.05 or P < 0.01 versus the homocysteine-injured group). These results suggest that quercetin has a protective effect on homocysteine-injured vascular endothelial cells by antioxidant and anti-inflammatory mechanisms.

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Cardiovasc Res. 2007 Jan 15;73(2):424-31. Epub 2006 Sep 20
The dietary flavonoid quercetin activates BKCa currents in coronary arteries via production of H2O2. Role in vasodilatation.
Cogolludo A, Frazziano G, Briones AM, Cobeño L, Moreno L, Lodi F, Salaices M, Tamargo J, Perez-Vizcaino F.
Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, 28040 Madrid, Spain.

OBJECTIVE: Large conductance Ca(2+)-activated K(+) channels (BKCa) regulate coronary artery tone in vivo, play a key role in blood pressure regulation, and have been suggested as novel potential drug targets in hypertension. Quercetin exerts systemic and coronary vasodilator effects in vitro and reduces blood pressure in several rat models of hypertension, and its consumption is associated with a lower mortality rate from coronary heart disease in epidemiological studies. We hypothesized that quercetin might activate BKCa channel in isolated myocytes from rat coronary arteries and that this mechanism might be involved in its coronary artery relaxant effects. METHODS: Membrane currents were measured using the whole-cell configuration of the patch-clamp technique. Contractile tension was recorded in rat coronary artery rings mounted in a myograph. RESULTS: Quercetin (>0.1 muM) increased the outward currents in the whole range of test potentials, hyperpolarized cell membranes, and increased the frequency of spontaneous transient outward currents (STOCs) carried by BKCa channels. These effects were abolished by the selective BKCa blocker iberiotoxin and by catalase. Quercetin increased dichlorofluorescein fluorescence in coronary arteries in a polyethylenglycol-catalase-sensitive manner, indicating that it increased cytosolic H(2)O(2). The membrane-permeable analogue of H(2)O(2)t-butylhydroperoxide mimicked the effects of quercetin on outward currents. The vasodilator effect of quercetin in isolated rat coronary arteries was partially inhibited by iberiotoxin. CONCLUSION: Quercetin increased BKCa currents via production of intracellular H(2)O(2). This effect is involved, at least partly, in the coronary vasodilator effects of quercetin.