Beta-Carotene Affects the Effects of Heme Oxygenase-1 in Isolated, Ischemic/Reperfused Rat Hearts: Potential Role of the Iron.

Beta-carotene (BC) is a well-known antioxidant. However, increasing evidence shows that under severe oxidative conditions, BC can become pro-oxidant, an effect that may be enhanced in the presence of iron (II). In our earlier studies, we observed that despite increasing heme oxygenase-1 (HO-1) levels in the heart, the protective effects of BC have been lost when it was used at a high concentration. Since iron releases from heme as a consequence of HO-1 activity, we hypothesized that the application of an iron-chelator (IC) would reverse the lost cardiac protection associated with an elevated HO-1 level. Thus, in the present study, we investigated the effects of desferrioxiamine (DFO) in isolated, ischemic/reperfused rat hearts after long-term treatment with vehicle or high-dose (HD) BC. Vehicle or 150 mg/bw kg daily doses of BC were administered to the rats for 4 weeks, and then their hearts were removed and subjected to 30 min of global ischemia (ISA) followed by 120 min of reperfusion (REP). During the experiments, cardiac function was registered, and at the end of the REP period, infarct size (IS) and HO-1 expression were measured. The results show that DFO treatment alone during REP significantly ameliorated postischemic cardiac function and decreased IS, although HO-1 expression was not increased significantly. In hearts isolated from BC-treated rats, no cardioprotective effects, despite an elevated HO-1 level, were observed, while DFO administration after ISA resulted in a mild improvement in heart function and IS. Our results suggest that iron could have a role whether BC exerts antioxidant or pro-oxidant effects in ISA/REP-injured hearts.

Basic Pharmacological Characterization of EV-34, a New H2S-Releasing Ibuprofen Derivative.

BACKGROUND: Cardioprotective effects of H2S are being suggested by numerous studies. Furthermore, H2S plays a role in relaxation of vascular smooth muscle, protects against oxidative stress, and modulates inflammation. Long-term high-dose use of NSAIDs, such as ibuprofen, have been associated with enhanced cardiovascular risk. The goal of the present work is the synthesis and basic pharmacological characterization of a newly designed H2S-releasing ibuprofen derivative. METHODS: Following the synthesis of EV-34, a new H2S-releasing derivative of ibuprofen, oxidative stability assays were performed (Fenton and porphyrin assays). Furthermore, stability of the molecule was studied in rat serum and liver lysates. H2S-releasing ability of the EC-34 was studied with a hydrogen sulfide sensor. MTT (3-(4,5-dimethylthiazol 2-yl)-2,5-(diphenyltetrazolium bromide)) assay was carried out to monitor the possible cytotoxic effect of the compound. Cyclooxygenase (COX) inhibitory property of EV-34 was also evaluated. Carrageenan assay was carried out to compare the anti-inflammatory effect of EV-34 to ibuprofen in rat paws. RESULTS: The results revealed that the molecule is stable under oxidative condition of Fenton reaction. However, EV-34 undergoes biodegradation in rat serum and liver lysates. In cell culture medium H2S is being released from EV-34. No cytotoxic effect was observed at concentrations of 10, 100, 500 µM. The COX-1 and COX-2 inhibitory effects of the molecule are comparable to those of ibuprofen. Furthermore, based on the carrageenan assay, EV-34 exhibits the same anti-inflammatory effect to that of equimolar amount of ibuprofen (100 mg/bwkg). CONCLUSION: The results indicate that EV-34 is a safe H2S releasing ibuprofen derivative bearing anti-inflammatory properties.

The Effects of Long-Term, Low- and High-Dose Beta-Carotene Treatment in Zucker Diabetic Fatty Rats: The Role of HO-1.

Nowadays, there is a growing interest in compounds derived from plants as potential raw materials for drug development. One of the most studied compounds is beta-carotene (BC). Several clinical studies can be found investigating the cardiovascular effects of BC, however, all these results are controversial. There is an increasing body of evidence showing that besides the well-known antioxidant properties, under strong oxidative circumstances, BC could become prooxidant as well. In this study, we investigated the effects of long-term, low- and high-dose BC treatment in ischemic/reperfused (ISA/REP) hearts isolated from Zucker diabetic fatty (ZDF) rats. The animals were treated with various daily doses of BC for 4 weeks and then hearts were isolated and subjected to 30 min of global ischemia (ISA) followed by 120 min of reperfusion (REP). Blood glucose levels were measured before, after two weeks, and at the end of the treatment. In isolated hearts, the myocardial function was registered. At the end of the reperfusion period, the infarct size (IS) and heme oxygenase-1 (HO-1) expression were measured. The results showed that a low dose of BC treatment significantly improved postischemic recovery, which was reflected in a decreased IS. Interestingly, when BC was applied at high concentrations, the observed protective effects were lost. Although BC treatment increased HO-1 expression, we did not observe a better heart function and/or decreased IS in the high-dose-treated group. Glucose tolerance tests showed a concentration-independent decrease in blood glucose levels. Our results suggest that long-term, low-dose BC treatment could be effective in the treatment of type-2-diabetes and related cardiovascular diseases.

Aged (Black) versus Raw Garlic against Ischemia/Reperfusion-Induced Cardiac Complications.

Recent evidence from studies suggests that aged black garlic also has an effect on health. The major aim of the present study is to compare the effect of raw and aged black garlic on postischemic cardiac recovery. Male Sprague Dawley rats were randomly divided into three groups. Animals of the first group were fed with raw garlic, animals of the second group received aged black garlic, while the third group served as vehicle-treated controls. Upon conclusion of the treatment, isolated hearts were undertaken to ischemia/reperfusion. Heart function and infarct size were measured and the level of HO-1 and iNOS were studied. Superior postischemic cardiac function and reduced infarct size in both garlic treated groups compared to the drug-free control group, indicated cardioprotective effects. However, no significant differences between the garlic treated groups were observed. Western blot analysis revealed that raw garlic enhanced the level of HO-1 before ischemia, while in ischemic samples, we found elevated HO-1 expression in both garlic treated groups. The level of iNOS was the same before ischemia in all groups, however, a markedly reduced iNOS level in ischemic/reperfused hearts originating from control and raw garlic treated animals was observed. Samples from aged black garlic treated animals demonstrated that the level of iNOS was not significantly reduced after ischemia/reperfusion. Taken together these results indicate that not only raw but also aged black garlic possess a cardioprotective effect.

Effects of Momordica charantia (Bitter Melon) on Ischemic Diabetic Myocardium.

Objective: A rat model is here used to test a hypothesis that Momordica charantia (Bitter melon (BM)) extract favorably alters processes in cardiovascular tissue and is systemically relevant to the pathophysiology of type 2 diabetes (T2DM) and related cardiovascular disease. Methods: Male Lean and Zucker Obese (ZO) rats were gavage-treated for six weeks with 400 mg/kg body weight bitter melon (BM) extract suspended in mucin-water vehicle, or with vehicle (Control). Animals were segregated into four treatment groups, 10 animals in each group, according to strain (Lean or ZO) and treatment (Control or BM). Following six-week treatment periods, peripheral blood was collected from selected animals, followed by sacrifice, thoracotomy and mounting of isolated working heart setup. Results: Body mass of both Lean and ZO rats was unaffected by treatment, likewise, peripheral blood fasting glucose levels showed no significant treatment-related effects. However, some BM treatment-related improvement was noted in postischemic cardiac functions when Lean, BM-treated animals were compared to vehicle treated Lean control rats. Treatment of Lean, but not ZO, rats significantly reduced the magnitude of infarcted zone in isolated hearts subjected to 30 min of ischemia followed by 2 h of working mode reperfusion. Immunohistochemical demonstration of caspase-3 expression by isolated heart tissues subjected to 30 min of ischemia followed by 2 h of reperfusion, revealed significant correlation between BM treatment and reduced expression of this enzyme in hearts obtained from both Lean and ZO animals. The hierarchy and order of caspase-3 expression from highest to lowest was as follows: ZO rats receiving vehicle > ZO rats receiving BM extract > Lean rats treated receiving vehicle > Lean rats administered BM extract. Outcomes of analyses of peripheral blood content of cardiac-related analytics: with particular relevance to clinical application was a significant elevation in blood of ZO and ZO BM-treated, versus Lean rats of total cholesterol (high density lipoprotein HDL-c + low density lipoprotein LDL-c), with an inferred increase in HDL-c/LDL-c ratio-an outcome associated with decreased risk of atherosclerotic disease. Conclusions: BM extract failed to positively affect T2DM- and cardiovascular-related outcomes at a level suggesting use as a standalone treatment. Nevertheless, the encouraging effects of BM in enhancement of cardiac function, suppression of post-ischemic/reperfused infarct size extent and capacity to modulate serum cholesterol, will likely make it useful as an adjuvant therapy for the management of T2DM and related cardiovascular diseases.

Cardiovascular effects of low versus high-dose beta-carotene in a rat model.

ß-carotene (BC), a lipid-soluble tetraterpene precursor to vitamin A, widely distributed in plants, including many used in human diet, has well-known health-enhancing properties, including reducing risk of and treatment for certain diseases. Nevertheless, BC may also act to promote disease through the activity of BC derivatives that form in the presence of external toxicants such as cigarette smoke and endogenously-produced reactive oxygen species. The present investigation evaluates the dose-dependent cardioprotective and possibly harmful properties of BC in a rat model. Adult male rats were gavage-fed BC for 4 weeks, at dosages of either 0, 30 or 150 mg/kg/day. Then, hearts excised from the animals were mounted in a "working heart" apparatus and subjected to 30 min of global ischemia, followed by 120 min of reperfusion. A panel of cardiac functional evaluations was conducted on each heart. Infarct size and total antioxidant capacity of the myocardium were assessed. Heart tissue content of heme oxygenase-1 (HO-1) by Western blot analysis; and potential direct cytotoxic effects of BC by MTT assay were evaluated. Hearts taken from rats receiving 30 mg/kg/day BC exhibited significantly improved heart function at lower reperfusion times, but lost this protection at higher BC dosage and longer reperfusion times. Myocardial HO-1 content was significantly elevated dose-responsively to both BC dosage. Finally, in vitro evaluation of BC on H9c2 cells showed that the agent significantly improved vitality of these cells in a dose range of 2.5-10 µM. Although data presented here do not allow for a comprehensive mechanistic explanation for reduced cardioprotection at high dose BC, it is speculated that since Fe2+ produced as a metabolite of HO-1 activity, may determine whether BC acts as an antioxidant or prooxidant agent, the strong induction of this enzyme in response to ischemia/reperfusion-induced oxidative stress may account for the high-dose BC loss of cardioprotection.

Orally delivered sour cherry seed extract (SCSE) affects cardiovascular and hematological parameters in humans.

In the present study, we investigated the effects of sour cherry seed extract (SCSE) on a variety of systemic processes that contribute to general health and viability of human subjects. The experiments were conducted according to a double-blind protocol in which six healthy individuals were administered 250-mg/day SCSE for 14 days, while four were treated with placebo. Peripheral blood was collected before and after the treatment period. Samples were analyzed for levels of selected cells, enzymes, or metabolites. Subjects that received SCSE showed increases in the values of mean cell volume, serum transferrin, mean peroxidase index, and representation of peripheral blood lymphocytes. On the other hand, decreases were observed in circulating neutrophils and ferritin levels. Changes observed in the present study do not fit into a clear pattern that might yield additional in-depth understanding of SCSE-mediated alterations in physiologic responses. The most encouraging result of the present study is the absence of any indication of toxicity by subjects consuming the extract.

Cardioprotection afforded by sour cherry seed kernel: the role of heme oxygenase-1.

Cardiovascular diseases are primary cause of death worldwide, particularly among populations with sedentary lifestyles and diets rich in animal products and processed foods. Currently, public health countermeasures to these disorders focus on costly and often marginally effective interventions administered only after the development of disease. These countermeasures are mainly palliative and fail to address the underlying causes of cardiac pathologies. Previously, the authors of this report have demonstrated that sour cherry seed kernel extract (SCSE), a nontoxic low-cost plant material, strongly preserves tissues through induction of heme oxygenase-1 (HO-1), a critical host antioxidant defense enzyme. This investigation seeks to characterize underlying mechanisms of SCSE-mediated tissue protection. Isolated hearts from Sprague-Dawley rats fed 30 mg·kg·d SCSE for 8 weeks, and untreated controls were mounted in a "working heart" apparatus and subjected to ischemia and reperfusion. A panel of cardiac functional evaluations was conducted on each heart. Infarct size assessments were made along with Western blot and immunohistochemical analysis for selected proteins involved in cardiovascular homeostasis. SCSE treatment was observed to improve postischemic cardiac functions and suppress infarct size. Analysis of the outcomes produced by this study is consistent with SCSE cardioprotection that involve interaction of Bcl-2 and HO-1.

Tocotrienols confer resistance to ischemia in hypercholesterolemic hearts: insight with genomics.

Most clinical trials with vitamin E could not lower cholesterol and thus, have been deemed unsuccessful. Recently, tocotrienols, isomers of vitamin E have been found to lower LDL levels. To explore if tocotrienols could be the drug target for vitamin E, rabbits were kept on cholesterol diet for 60 days supplemented with tocotrienol-α, tocotrienol-δ, and tocotrienol-γ for the last 30 days. The serum cholesterol levels (in mmol/l) were 24.4 (tocotrienol-α), 34.9 (tocotrienol-δ), 19.8 (tocotrienol-γ) vs. 39.7 (control). Left ventricular function including aortic flow and developed pressure exhibited significantly improved recovery with tocotrienol-γ and -α, but not with tocotrienol-δ. The myocardial infarct size showed a similar pattern: 33% (tocotrienol-α), 23% (tocotrienol-γ), and 47% (tocotrienol-δ). To examine the molecular mechanisms of cardioprotective effects, gene expression profile was determined using Atlas 1.2/1.2II followed by determination of gene profiles using PedQuest 8.3 software. Based on genomic profiles, the following cholesterol-related proteins were examined: FABP, TGF-ß (cholesterol suppresses TGF-ß), ET-1 (increased by hypercholesterolemia), SPOT 14 (linked with hypercholesterolemia), and matrix metalloproteinase (MMP) 2 and MMP9 (cholesterol regulates MMP2 and MMP9 expression) in the heart. Consistent with the cardioprotective effects of tocotrienol-α and -γ, these two isomers reduced ET-1, decreased MMP2 and MM9, increased TGF-ß and reduced SPOT 14, while tocotrienol-δ had no effects. The results of the present study demonstrate that the two isomers of tocotrienols, α and γ, render the hypercholesterolemic hearts resistant to ischemic reperfusion injury by lowering several hypercholesterolemic proteins including MMP2, MMP9, ET-1, and SPOT 14 and upregulating TGF-ß.

Summative interaction between astaxanthin, Ginkgo biloba extract (EGb761) and vitamin C in suppression of respiratory inflammation: a comparison with ibuprofen.

In this study, combinations of Ginkgo biloba leaf extract (EGb761) plus the carotenoid antioxidant astaxanthin (ASX) and vitamin C were evaluated for a summative dose effect in the inhibition of asthma-associated inflammation in asthmatic guinea-pigs. Ovalbumin-sensitized Hartley guinea-pigs challenged with ovalbumin aerosol to induce asthma, were administered EGb761, ASX, vitamin C or ibuprofen. Following killing, bronchoalveolar lavage (BAL) fluid was evaluated for inflammatory cell infiltrates and lung tissue cyclic nucleotide content. Each parameter measured was significantly altered to a greater degree by drug combinations, than by each component acting independently. An optimal combination was identified that included astaxanthin (10 mg/kg), vitamin C (200 mg/kg) and EGb761 (10 mg/kg), resulting in counts of eosinophils and neutrophils each 1.6-fold lower; macrophages 1.8-fold lower, cAMP 1.4-fold higher; and cGMP 2.04-fold higher than levels in untreated, asthmatic animals (p < 0.05). In conclusion, EGb761, ASX and vitamin C are shown here to interact summatively to suppress inflammation with efficacy equal to or better than ibuprofen, a widely used non-steroidal antiinflammatory drug (NSAID). Such combinations of non-toxic phytochemicals constitute powerful tools for the prevention of onset of acute and chronic inflammatory disease if consumed regularly by healthy individuals; and may also augment the effectiveness of therapy for those with established illness.

Isolation and analysis of bioactive constituents of sour cherry (Prunus cerasus) seed kernel: an emerging functional food.

A plant-based diet reduces the risk for the development of several chronic diseases, such as ischemic heart disease or cancer due to natural compounds found in plants. Numerous cereals, berries, fruits, and vegetables, including sour cherry (Prunus cerasus), which is a favored fruit worldwide, contain biological active components. The antioxidant components of the sour cherry seed kernel have not been investigated until now. The aim of our study was to isolate and analyze the bioactive constituents of sour cherry seed kernel. We separated the oil fraction of the kernel; then the remaining solid fraction was dried, and the oil-free kernel extract was further analyzed. Our results show that sour cherry seed kernel oil contains vegetable oils including unsaturated fatty acids, oleic acids, alpha-tocopherol, tocotrienols, and tocopherol-like components. The components of the solid fraction include various bioactive structures such as polyphenols, flavonoids, vegetable acids, and pro- and anthocyanidins, which could have useful therapeutic effects in the prevention of various vascular diseases.

Protective role of air potato (Dioscorea bulbifera) of yam family in myocardial ischemic reperfusion injury.

Hydroalcoholic extract of Dioscorea bulbifera (DB), a yam variety called air potato, was tested for its protective effect on myocardial ischemic/reperfusion (I/R) injury in rats due to apoptosis and necrosis. Myocardial I/R injury was induced by 30 min ischemia followed by 2 h reperfusion by perfusing isolated rat hearts with Krebs Henseilet bicarbonate (KHB) buffer in a Langendorff set up. Pretreatment of DB (150 mg kg(-1) body weight) for 30 days significantly reduced myocardial infarct size and improved the ventricular function (aortic flow and coronary flow, LVDP, LVmax dp/dt). Role of DB on apoptosis was also evaluated by determining caspase 3 as well as by examining pro-apoptotic and anti-apoptotic proteins Bax and Bcl2 by Western blot analysis followed by TUNEL assay. DB also prevented I/R-mediated down regulation of survival protein Akt and HO-1. Our results indicated that Dioscorea bulbifera could ameliorate myocardial ischemia and reperfusion injury by improving ventricular function and inhibition of cardiomyocyte necrosis and apoptosis.

Freshly crushed garlic is a superior cardioprotective agent than processed garlic.

In this study, we compared the cardioprotective effects of freshly crushed garlic vis-a-vis that of processed garlic. Two groups of rats were gavaged with respective garlic preparations while the control group received vehicle only. After 30 days, all of the rats were sacrificed and isolated the hearts were subjected to 30 min ischemia followed by 2 h of reperfusion. Both of the garlic preparations provided cardioprotection, but superior cardiac performance was noticed for those fed with freshly crushed garlic. Consistent with these results, the freshly crushed garlic group displayed significantly greater phosphorylation of antiapoptotic ERK1/2 proteins, reduced Bax/Bcl-2 ratio, and reduced phosphorylation of proapoptotic p-38MAPK and JNK. Moreover, the survival signaling network consisting of Akt-FoxO1 was increased in the freshly crushed garlic treated hearts. Freshly crushed garlic, but not the processed garlic, showed enhanced redox signaling as evident by increased level of p65 subunit of NFkappaB, Nrf2, and enhanced GLUT 4, PPARalpha, and PPARdelta. The results thus show that although both freshly crushed garlic and processed garlic provide cardioprotection, the former has additional cardioprotective properties presumably due to the presence of H2S.

Potential role of Borreria hispida in ameliorating cardiovascular risk factors.

Borreria hispida (BHE), a weed of Rubiaceae family, is being used from time immemorial as an alternative therapy for diabetes. To evaluate the scientific background of using BHE as therapy to reduce cardiovascular risk, a group of rats were given BHE for a period of 30 days, whereas control animals were given the vehicle only. The animals were sacrificed, the hearts were isolated, and perfused with buffer. All the hearts were subjected to 30-minute ischemia followed by 2-hour reperfusion. Compared with vehicle-treated rats, BHE-treated rat hearts showed improved post-ischemic ventricular function and exhibited reduced myocardial infarct size and cardiomyocyte apoptosis. The level of cytochrome c expression and caspase 3 activation was also reduced. BHE elevated antiapoptotic proteins Bcl-2 and heme oxygenase-1 and stimulated the phosphorylation of survival protein Akt simultaneously decreasing the apoptotic proteins Bax and Src. In addition, BHE enhanced the protein expression of peroxisome proliferator-activated receptor-gamma, peroxisome proliferator-activated receptor-delta, and Glut-4, probably revealing the antiobese and antidiabetic potential of BHE. These results indicate that treatment with BHE improves cardiac function and ameliorates various risk factors associated with cardiac disease, suggesting that BHE can be considered as a potential plant-based nutraceutical and pharmaceutical agent for the management of cardiovascular diseases.

Coenzyme Q9 provides cardioprotection after converting into coenzyme Q10.

Coenzyme Q10 (CoQ10) has been extensively studied as adjunctive therapy for ischemic heart disease, and its cardioprotective ability is well-established. The mitochondrial respiratory chain contains several coenzymes, including CoQ1, CoQ2, CoQ4, CoQ6, CoQ7, CoQ8, CoQ9, and CoQ10. It is not known whether other CoQs, especially CoQ9, is equally cardioprotective as CoQ10. The present study was designed to determine if CoQ 9 could protect guinea pig hearts from ischemia reperfusion injury. Guinea pigs were randomly divided into three groups: groups I and II were fed CoQ 9 and CoQ10, respectively, for 30 days while group III served as control. After 30 days, the guinea pigs were sacrificed and isolated hearts were perfused via working mode were subjected to 30 min ischemia followed by 2 h of reperfusion. Cardioprotection was assessed by evaluating left ventricular function, ventricular arrhythmias, myocardial infarct size, and cardiomyocyte apoptosis. Samples of hearts were examined for the presence of CoQ9 and CoQ10. The results demonstrated that both CoQ9 and CoQ10 were equally cardioprotective, as evidenced by their abilities to improve left ventricular performance and to reduce myocardial infarct size and cardiomyocyte apoptosis. High performance liquid chromatographic (HPLC) analysis revealed that a substantial portion of CoQ9 had been converted into CoQ10. The results indicate that CoQ9 by itself, or after being converted into CoQ10, reduced myocardial ischemia/reperfusion-induced injury.

Cardioprotection with alpha-tocopheryl phosphate: amelioration of myocardial ischemia reperfusion injury is linked with its ability to generate a survival signal through Akt activation.

The emerging potential of alpha-tocopheryl phosphate, a phosphoric acid ester of alpha-tocopherol, in health benefits was tested gavaging this compound (5 mg/kg body wt) to a group of rats for a period of thirty days while the control rats were given water only. After thirty days, the rats were sacrificed, the hearts excised, and the isolated hearts were perfused by working mode. Both control and experimental hearts were subjected to 30-min global ischemia followed by 2 h of reperfusion. The tocopheryl phosphate fed rats exhibited significant cardioprotection as evidenced by improved ventricular performance and reduced myocardial infarct size and cardiomyocyte apoptosis. Supplementation with alpha-tocopheryl phosphate converted MAP kinase-induced death signal into a survival signal by enhancing anti-apoptotic p42/44 ERK kinase and p38 MAPKbeta and reducing pro-apoptotic proteins p38 MAPKalpha and JNK. In concert, the phosphorylation of pro-apoptotic c-Src was also reduced. Tocopheryl phosphate increased the DNA binding of the redox-sensitive transcription factor NFkappaB and potentiated the activation of anti-death protein Bcl-2 and survival signaling protein Akt. The results of this study demonstrated for the first time that tocopheryl phosphate could ameliorate myocardial ischemic reperfusion injury by converting ischemia/reperfusion-mediated death signal into a survival signal by modulating MAP kinase signaling.

Cardioprotection with palm oil tocotrienols: comparision of different isomers.

A recent study from our laboratory indicated the cardioprotective ability of the tocotrienol-rich fraction (TRF) from red palm oil. The present study compared cardioprotective abilities of different isomers of tocotrienol against TRF as recently tocotrienol has been found to function as a potent neuroprotective agent against stroke. Rats were randomly assigned to one of the following groups: animals were given, by gavage, either 0.35%, 1%, or 3.5% TRF for two different periods of time (2 or 4 wk) or 0.03, 0.3, and 3 mg/kg body wt of one of the isomers of tocotrienol (alpha, gamma, or delta) for 4 wk; control animals were given, by gavage, vehicle only. After 2 or 4 wk, rats were killed, and their hearts were then subjected to 30 min of global ischemia followed by 2 h of reperfusion. Dose-response and time-response experiments revealed that the optimal concentration for TRF was 3.5% TRF and 0.3 mg/kg body wt of tocotrienol given for 4 wk. TRF as well as all the isomers of tocotrienol used in our study provided cardioprotection, as evidenced by their ability to improve postischemic ventricular function and reduce myocardial infarct size. The gamma-isoform of tocotrienol was the most cardioprotective of all the isomers followed by the alpha- and delta-isoforms. The molecular mechanisms of cardioprotection afforded by tocotrienol isoforms were probed by evaluating their respective abilities to stabilize the proteasome, allowing it to maintain a balance between prodeath and prosurvival signals. Our results demonstrated that tocotrienol isoforms reduced c-Src but increased the phosphorylation of Akt, thus generating a survival signal.

Cardioprotective mechanisms of Prunus cerasus (sour cherry) seed extract against ischemia-reperfusion-induced damage in isolated rat hearts.

The effects of kernel extract obtained from sour cherry (Prunus cerasus) seed on the postischemic cardiac recovery were studied in isolated working rat hearts. Rats were treated with various daily doses of the extract for 14 days, and hearts were then isolated and subjected to 30 min of global ischemia followed by 120 min of reperfusion. The incidence of ventricular fibrillation (VF) and tachycardia (VT) fell from their control values of 92% and 100% to 50% (not significant) and 58% (not significant), 17% (P<0.05), and 25% (P<0.05) with the doses of 10 mg/kg and 30 mg/kg of the extract, respectively. Lower concentrations of the extract (1 and 5 mg/kg) failed to significantly reduce the incidence of VF and VT during reperfusion. Sour cherry seed kernel extract (10 and 30 mg/kg) significantly improved the postischemic recovery of cardiac function (coronary flow, aortic flow, and left ventricular developed pressure) during reperfusion. We have also demonstrated that the extract-induced protection in cardiac function significantly reflected in a reduction of infarct size. Immunohistochemistry indicates that a reduction in caspase-3 activity and apoptotic cells by the extract, beside other potential action mechanisms of proanthocyanidin, trans-resveratrol, and flavonoid components of the extract, could be responsible for the cardioprotection in ischemic-reperfused myocardium.