Biomedical subjects

Nilanjana Maulik

Publications and source records attributed to Nilanjana Maulik.

At least 19 recordsLinked to original sources

PubMed2006

Statin and resveratrol in combination induces cardioprotection against myocardial infarction in hypercholesterolemic rat.

Hypercholesterolemia (HC) is a common health problem that significantly increases risk of cardiovascular disease. Both statin (S) and resveratrol (R) demonstrated cardioprotection through nitric oxide-dependent mechanism. Therefore, the present study was undertaken to determine whether combination therapy with statin and resveratrol is more cardioprotective than individual treatment groups in ischemic rat heart model. The rats were fed with 2% high cholesterol diet and after 8 weeks of high cholesterol diet the animals were treated with statin (1 mg/kg bw/day) and resveratrol (20 mg/kg bw/day) for 2 weeks. The rats were assigned to: (1) Control (C), (2) HC, (3) HCR, (4) HCS and (5) HCRS. The hearts, subjected to 30-min global ischemia followed by 120-min reperfusion were used as experimental model. The left ventricular functional recovery (+dp/dt(max)) was found to be significantly better in the HCRS (1926+/-43), HCR (1556+/-65) and HCS (1635+/-40) compared to HC group (1127+/-16). The infarct sizes in the HCRS, HCS and HCR groups were 37+/-3.6, 43+/-3.3 and 44+/-4.2 respectively compared to 53+/-4.6 in HC. The lipid level was found to be decreased in all the treatment groups when compared to HC more significantly in HCS and HCRS groups when compared to HCR. Increased phosphorylation of Akt and eNOS was also observed in all the treatment groups resulting in decreased extent of cardiomyocyte apoptosis but the extent of reduction in apoptosis was more significant in HCRS group compared to all other groups. In vivo rat myocardial infarction (MI) model subjected to 1 week of permanent left descending coronary artery (LAD) occlusion documented increased capillary density in HCR and HCRS treated group when compared to HCS treatment group. We also documented increased beta-catenin translocation and increased VEGF mRNA expression in all treatment groups. Thus, we conclude that the acute as well as chronic protection afforded by combination treatment with statin and resveratrol may be due to pro-angiogenic, anti-hyperlipidemic and anti-apoptotic effects and long-term effects may be caused by increased neo-vascularization of the MI zone leading to less ventricular remodeling.

Animals↗

PubMed2006

Secoisolariciresinol diglucoside: relevance to angiogenesis and cardioprotection against ischemia-reperfusion injury.

Therapeutic angiogenesis represents a novel approach for the prevention and treatment of ischemic heart disease. This study examined a novel method of stimulating myocardial angiogenesis using secoisolariciresinol diglucoside (SDG), a plant lignan isolated from flaxseed. SDG has been shown to decrease serum cholesterol and reduce the extent of atherosclerosis. In the present study, the angiogenic properties of SDG were investigated in three different models. First, in the in vitro model, human coronary arteriolar endothelial cells (HCAEC) treated with SDG (50 and 100 microM) showed a significant increase in tubular morphogenesis compared with control. Western blot analysis indicated an increased expression of vascular endothelial growth factor (VEGF), kinase insert domain-containing receptor (KDR), Flt-1, angiopoietin-1 (Ang-1), Tie-1, and phosphorylated endothelial nitric oxide synthase (p-eNOS) in the SDG-treated cells. Second, in the ex vivo ischemia/reperfusion model, SDG-treated rats (20 mg/kg b.wt./day for 2 weeks orally) showed an increased level of aortic flow and functional recovery after 2 h of reperfusion following 30 min of ischemia compared with the control group [dP/dt (mm Hg/s) of 2110 +/- 35 versus 1752 +/- 62]. SDG reduced infarct size compared with the control group by 32% (38 versus 26%) and also decreased cardiomyocyte apoptosis. Increased protein expression of VEGF, Ang-1, and p-eNOS was also observed in the SDG-treated group. Third, in the in vivo myocardial infarction model, SDG increased capillary density and myocardial function as evidenced by increased fractional shortening and ejection fraction. In conclusion, these results suggest that SDG has potent angiogenic and antiapoptotic properties that may contribute to its cardioprotective effect in ischemic models.

Animals↗

PubMed2006

Sildenafil induces angiogenic response in human coronary arteriolar endothelial cells through the expression of thioredoxin, hemeoxygenase and vascular endothelial growth factor.

This study was undertaken to investigate the effect of phosphodiesterase-5 (PDE5) inhibitor, sildenafil, on angiogenic response in human coronary arteriolar endothelial cells (HCAEC). The cells exposed to sildenafil (1-20 microM) demonstrated significantly accelerated tubular morphogenesis with the induction of thioredoxin-1 (Trx-1), hemeoxygenase-1 (HO-1) and VEGF. Sildenafil induced VEGF and angiopoietin specific receptors such as KDR, Tie-1 and Tie-2. This angiogenic response was repressed by tinprotoporphyrin IX (SnPP), an inhibitor of HO-1 enzyme activity. Sildenafil below 1 muM has no angiogenic effect as evidenced by reduced tuborogenesis. Sildenafil along with SnPP inhibited both VEGF and Angiopoietin-1 (Ang-1) protein expression. Therefore our results demonstrated for the first time that sildenafil is a very potent pro-angiogenic factor.

Arterioles↗

PubMed2006

Redox regulation of angiotensin II preconditioning of the myocardium requires MAP kinase signaling.

A recent study documented reactive oxygen species (ROS), generated through NADPH oxidase by angiotensin II (Ang II) with the activation of NADPH oxidase subunits, p22phox and gp91phox, to be responsible for the preconditioning effect of Ang II. The present study was designed to determine if similar to ischemic preconditioning (PC), mitogen-activated protein (MAP) kinases are also involved in Ang II PC of the heart. Isolated working rat hearts were perfused for 15 min with KHB (Krebs-Henseleit bicarbonate) buffer containing Ang II in the absence or presence of an Erk (1/2) inhibitor, PD 098059, a p38MAPK inhibitor, SB 202190, a JNK inhibitor, SP 600125 or a ROS scavenger, N-acetyl cysteine (NAC). All hearts were subsequently subjected to 30 min global ischemia followed by 2 h reperfusion with KHB buffer only. Cardioprotection was examined by determining infarct size, cardiomyocyte apoptosis and ventricular recovery. Redox and MAP kinase regulation were studied by determining the survival signaling mediated by Akt and Bcl-2. In consistent with previous results, Ang II preconditioned the heart as evidenced by improved postischemic ventricular recovery and reduced infarct size and decreases cardiomyocyte apoptosis. Ang II phosphorylated both Akt, Bcl-2 and Bad, which was blocked by NAC, PD 098059 or SP 600125, but not by SB 202190. NAC, PD 098059 and SP600125, but not SB202190, also abolished the cardioprotective effect of Ang II preconditioning. The results indicate that Ang II preconditioning is potentiated through MAP kinases that are regulated by redox signaling.

Angiotensin II↗

PubMed2006

The effect of Euryale ferox (Makhana), an herb of aquatic origin, on myocardial ischemic reperfusion injury.

Fox nut or gorgon nut (Euryale ferox--Family Nymphaeaceae), popularly known as Makhana, has been widely used in traditional oriental medicine to cure a variety of diseases including kidney problems, chronic diarrhea, excessive leucorrhea and hypofunction of the spleen. Based on the recent studies revealing antioxidant activities of Euryale ferox and its glucosides composition, we sought to determine if Euryale ferox seeds (Makhana) could reduce myocardial ischemic reperfusion injury. Two different models were used: acute model, where isolated rat hearts were preperfused for 15 min with Krebs Henseleit bicarbonate (KHB) buffer containing three different doses of makhana (25, 125 or 250 microg/ml) followed by 30 min of ischemia and 2 h of reperfusion; and chronic model, where rats were given two different doses of makhana (250 and 500 mg/kg/day) for 21 days, after which isolated hearts were subjected to 30 min of ischemia followed by 2 h of reperfusion. In both cases, the hearts of the Makhana treated rats were resistant to ischemic reperfusion injury as evidenced by their improved post-ischemic ventricular function and reduced myocardial infarct size. Antibody array technique was used to identify the cardioprotective proteins. The Makhana-treated hearts had increased amounts of thioredoxin-1 (Trx-1) and thioredoxin-related protein-32 (TRP32) compared to the control hearts. Western blot analysis confirmed increased expression of TRP32 and thioredoxin proteins. In vitro studies revealed that Makhana extracts had potent reactive oxygen species scavenging activities. Taken together, the results of this study demonstrate cardioprotective properties of Makhana and suggest that such cardioprotective properties may be linked with the ability of makhana to induce TRP32 and Trx-1 proteins and to scavenge ROS.

Animals↗

PubMed2006

Potentiation of a survival signal in the ischemic heart by resveratrol through p38 mitogen-activated protein kinase/mitogen- and stress-activated protein kinase 1/cAMP response element-binding protein signaling.

Resveratrol (3,4',5-trihydroxy-trans-stilbene), a naturally occurring polyphenolic compound found abundantly in grape skins and red wines, has been found to pharmacologically precondition the heart against ischemia reperfusion injury through the potentiation of a survival signal involving cAMP response element-binding protein-dependent phosphatidylinositol 3-kinase-Akt-BclII pathway. The present study was designed to determine whether, similar to ischemic preconditioning, resveratrol uses mitogen-activated protein kinases (MAPKs) as upstream signaling targets. The isolated rat hearts were preperfused for 15 min with Krebs-Henseleit bicarbonate buffer in the absence (control) or presence of extracellular signal-regulated kinase (ERK) 1/2 inhibitor 2'-amino-3'-methoxyflavone (PD98059), p38 MAPK inhibitor 4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)-1H-imidazole (SB-202190), mitogen- and stress-activated protein kinase 1 (MSK-1) inhibitor N-[2-(4-bromocinnamylamino)ethyl]-5-isoquinoline (H89), protein kinase A inhibitor (9S,10S,12R)-2,3,9,10,11,12-hexahydro-10hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3fg: 3',2',1'-kl]-pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylic acid hexyl ester (KT5720), resveratrol only, resveratrol plus PD98059, resveratrol plus SB-202190, resveratrol plus H89, or resveratrol plus KT5720. Consistent with previous reports, resveratrol provided cardioprotection as evidenced by its ability to improve postischemic ventricular function, reduction of myocardial infarct size, and cardiomyocyte apoptosis. The cardioprotection afforded by resveratrol was partially abolished with PD98059 or SB-202190, suggesting that ERK1/2 and p38 MAPK play roles in resveratrol-mediated preconditioning. An MSK-1 inhibitor, H89, abolished resveratrol-mediated preconditioning, indicating MSK-1 to be the downstream target molecule for both ERK1/2 and p38 MAPK. KT5720 had no effect on resveratrol-mediated cardioprotection. Corroborating these results, Western blot analysis revealed phosphorylation of ERK1/2, p38 MAPK, MAPK-activated protein (MAPKAP) kinase 2, and MSK-1 with resveratrol and inhibition of phosphorylation with corresponding inhibitors. These results showed for the first time that resveratrol triggers an MAPK signaling pathway involving ERK1/2 and p38 MAPK, the former using MSK-1 as the downstream target and the latter, using both MAPKAP kinase 2 and MSK-1 as downstream targets.

Animals↗

PubMed2006

Cardiac genomic response following preconditioning stimulus.

This review focuses on the genomic response following a preconditioning stimulus. Initial studies demonstrated that classical ischemic preconditioning mediated by cyclic episodes of short durations of reversible ischemia and reperfusion could result in the reprogramming of gene expression. Some of these genes are translated into proteins during the late preconditioning or so-called "second window of protection". Subsequent studies determined a unique similarity of the expressed gene profiles between diverse varieties of preconditioning including ischemic/hypoxic, heat shock, and oxidative stress. The most common genes that are expressed by virtually any kind of stress conditioning include antioxidants like superoxide dismutase, glutathione peroxidase and heme oxygenase and heat shock proteins such as HSP70. At a later date, differential display and subtractive hybridization techniques revealed the identities of many other genes including those belonging to mitochondrial respiratory chain such as ATPases. More recently, gene array profiles using gene chips determined several other genes triggered by preconditioning including the mitochondrial genes. The results of the studies present in the literature clearly indicate the existence of a strong resemblance between the patterns of gene expression profiles induced by diverse preconditioning stimuli, oxidative stress being situated at the cross-roads of all forms of the stresses. Redox signaling appears to be responsible for the conversion of the ischemia/reperfusion-induced "death signal" into preconditioning-mediated "survival signal".

Animals↗

PubMed2006

Enhanced cardiovascular function and energy level by a novel chromium (III)-supplement.

The impetus for the novel Energy Formula (EF) which combines the niacin-bound chromium (III) (0.45%) (NBC), standardized extract of Withania somnifera extracts (10.71%), caffeine (22.76%), D-ribose (10.71%) and selected amino acids such as phenylalanine, taurine and glutamine (55.37%) was based on the knowledge of the cardioprotective potentials of the Withania somnifera extract, caffeine and D-ribose as well as their abilities to increase energy levels and the abilities of amino acids to increase the muscle mass and energy levels. The effect of oral supplementation of EF on the safety, myocardial energy levels and cardioprotective ability were investigated in an ischemic-reperfused myocardium model in both male and female Sprague-Dawley rats over 90 days trial period. At the completion of 90 days, the EF-treated male and female rats gained 9.4% and 3.1% less body weights, respectively, as compared to their corresponding control groups. No significant difference was found in the levels of lipid peroxidation and activities of hepatic Aspartate transaminase, Alanine transaminase and Alkaline phosphatase in EF treatment when compared with control animals. The male and female rat hearts were subjected to 30 min of global ischemia followed by 2 h of reperfusion at 30 and 90 days of EF treatment. Cardiovascular functions including heart rate, coronary flow, aortic flow, dp/dt(max), left ventricular developed pressure (LVDP) and infarct size were monitored. The levels of myocardial adenosine triphosphate (ATP), creatine phosphate (CP), phospho-adenosine monophosphate kinase (p-AMPK) levels, were analyzed at the end of 30 and 90 days of treatment. Significant improvement was observed in all parameters in the EF treatment groups as compared to their corresponding controls. Thus the niacin-bound chromium (III) based energy formula is safe and effective supplement to boost energy levels and cardioprotection.

Adenosine Monophosphate↗

PubMed2006

Attenuation of ischemia/reperfusion injury in rats by the anti-inflammatory action of resveratrol.

Resveratrol (trans-3,4',5-trihydroxystilbene, CAS 501-36-0), a natural antioxidant and polyphenol found in grapes and wine, has been found to pharmacologically precondition the heart in nitric oxide (NO)-dependent manner. In the vascular system, NO functions as an endogenous inhibitor of leukocyte chemotaxis, adherence, and activation. The present study was designed to determine if resveratrol, through NO, can block the proadhesive molecules generated in the ischemic reperfused myocardium. Isolated hearts were prepared from properly anesthetized rats, and mounted on a Langendorff apparatus. The hearts were randomly assigned to one of the three groups: (i) control, (ii) resveratrol, and (iii) resveratrol + NG-nitro-L-arginine ethyl ester (L-NAME). The hearts were perfused in the absence (n = 6) or presence of 10 micromol/L resveratrol (n=6) or resveratrol + L-NAME (n = 6) for 15 min. All the hearts were then subjected to 30 min ischemia followed by 2 h of reperfusion. Ventricular function was monitored, infarct size and apoptotic cell death measured, and the proadhesive molecules and malonaldehyde formation determined in the perfusate. Resveratrol significantly improved postischemic ventricular function and reduced myocardial infarct size compared to the non-treated control group. The amount of proadhesive molecules including soluble intracellular adhesion molecule-1 (sICAM-1), endothelial leukocyte adhesion molecule-1 (sE-Selectin) and vascular cell adhesion molecule-1 (sVCAM-1) were each significantly decreased during reperfusion in the resveratrol group. L-NAME, a NO blocker, completely abolished such beneficial effects of resveratrol. The results support an anti-inflammatory action of resveratrol through a NO-dependent mechanism.

Animals↗

PubMed2006

Resveratrol in cardioprotection: a therapeutic promise of alternative medicine.

Resveratrol, a polyphenol phytoalexin, possesses diverse biochemical and physiological actions, including estrogenic, antiplatelet, and anti-inflammatory properties. Several recent studies determined the cardioprotective abilities of resveratrol. Both in experiments (acute) and in chronic models, resveratrol attenuates myocardial ischemic reperfusion injury, atherosclerosis, and reduces ventricular arrhythmias. It appears that resveratrol-mediated cardioprotection is achieved through the preconditioning effect (the best yet devised method of cardioprotection), rather than direct protection. Thus, resveratrol likely fulfills the definition of a pharmacological preconditioning compound and gives hope to the therapeutic promise of alternative medicine.

Antioxidants↗

PubMed2006

Niacin-bound chromium enhances myocardial protection from ischemia-reperfusion injury.

A novel niacin-bound, chromium-based energy formula (EF; InterHealth Nutraceuticals, Benicia, CA) has been developed in conjunction with D-ribose, caffeine, ashwagandha extract (containing 5% withanolides), and selected amino acids. We have assessed the efficacy of oral administration of EF (40 mg x kg body wt(-1) x day(-1)) in male and female rats over a period of 90 consecutive days on the cardiovascular and pathophysiological functions in an isolated rat heart model. After 30, 60, and 90 days of treatment with EF, the hearts of male and female rats were subjected to 30 min of global ischemia followed by 2 h of reperfusion and were measured for myocardial ATP, creatine phosphate (CP), phosphorylated AMP kinase (p-AMPK), and heat shock proteins. Myocardial ATP and CP levels were increased in both male and female rats after EF treatment compared with the controls. Western blot analyses were performed to quantify the expression of stress-related proteins such as heat shock proteins (HSP-70, -32, and -25) and are found to be increased in both male and female rats after EF treatment. The p-AMPK level, which is a sensor for the energy state in various cell types, was also found to be increased after treatment with EF in both male and female rats. Aortic flow, maximum first derivative of developed pressure, left ventricular developed pressure, and infarct size were observed after ischemia-reperfusion and found to be significantly improved in EF-treated rats compared with control animals. Thus EF demonstrated long-term safety as well as exhibiting significant cardioprotective ability during ischemia and reperfusion injury by increased energy production, improved cardiac function, and reduced infarct size.

Adenosine Triphosphate↗

PubMed2006

Resveratrol ameliorates myocardial damage by inducing vascular endothelial growth factor-angiogenesis and tyrosine kinase receptor Flk-1.

In our study, resveratrol (polyphenol) has been identified as a very important stimulus/agent for the induction of new vessel growth. Occlusion of a main coronary depletes the blood supply to the myocardium and subsequently reduces cardiac function, which ultimately leads to heart failure. Progressive, chronic coronary artery occlusion has been shown to induce development of collateral arteries to re-establish and maintain blood flow to the myocardium at risk via the growth of new capillary vessels or angiogenesis. Studies from our laboratory, as well as from others, have already confirmed the protective role of collaterals against myocardial ischemia and cell death. We have successfully demonstrated in rat myocardial infarction (MI) model an effect of resveratrol on significant upregulation of the protein expression profiles of vascular endothelial growth factor (VEGF) and its tyrosine kinase receptor Flk-1, 3 wk after MI. Pretreatment with resveratrol also increased nitric-oxide synthase (inducible NOS and endothelial NOS) along with increased antiapoptotic and proangiogenic factors nuclear factor (NF)-kappaB and specificity protein (SP)-1. We also were able to demonstrate increased capillary density as well as improved left ventricular function by pharmacological preconditioning with resveratrol 3 wk after MI.

Angiogenesis Inducing Agents↗

PubMed2006

Angiotensin preconditioning of the heart: evidence for redox signaling.

Angiotensin II (Ang II) has been found to exert preconditioning-like effect on mammalian hearts. Diverse mechanisms are known to exist to explain the cardioprotective abilities of Ang II preconditioning. The present study hypothesized, based on the recent report that Ang II generates reactive oxygen species (ROS) through NADPH oxidase, that Ang II preconditioning occurs through redox cycling. To test this hypothesis, a group of rat hearts was treated with Ang II in the absence or presence of an NADPH oxidase inhibitor, apocynin; or a cell-permeable ROS scavenger, N-acetyl cysteine (NAC). Ang II pretreatment improved postischemic ventricular recovery; reduced myocardial infarction; and decreased the number of cardiomyocyte apoptosis, indicating its ability to precondition the heart against ischemic injury. Both apocynin and NAC almost abolished the preconditioning ability of Ang II. Ang II resulted in increase in ROS activity in the heart, which was reduced by either NAC or apocynin. Ang II also increased both the NADPH oxidase subunits gp91 phox and p22phox mRNA expression, which was abolished with apocynin and NAC. Our results thus demonstrate that the Ang II preconditioning was associated with enhanced ROS activities and increased NADPH oxidase subunits p22phox and gp91phox expression. Both NAC and apocynin reduced ROS activities simultaneously abolishing preconditioning ability of Ang II, suggesting that Ang II preconditioning occurs through redox cycling. That both NAC and apocynin reduced ROS activities and abolished Ang II-mediated increase in p22phox and gp91phox activity further suggest that such redox cycling occurs via both NADPH oxidase-dependent and -independent pathways.

Acetophenones↗

PubMed2005

Glycogen synthase kinase-3beta/beta-catenin promotes angiogenic and anti-apoptotic signaling through the induction of VEGF, Bcl-2 and survivin expression in rat ischemic preconditioned myocardium.

Ischemic preconditioning (IP) enhances vascular endothelial growth factor (VEGF), Bcl-2 and survivin expression after myocardial infarction (MI). Mechanisms of angiogenic and anti-apoptotic effects due to IP still remain unclear. The present study attempts to address whether GSK-3beta-beta-catenin signaling in turn interacts with T-cell transcription factor/lymphoid-enhancer binding factor (TCF/LEF) and regulates these genes in the ischemic preconditioned myocardium. In a rat MI model with permanent occlusion of left anterior descending coronary artery (LAD), IP (four cycles of 4-min of ischemia and 4-min of reperfusion) significantly phosphorylated and inhibited GSK-3beta and accumulated beta-catenin in the cytosol and nucleus. Wortmannin, a PI-3 kinase inhibitor, repressed this effect in our model. We examined whether pretreatment with GSK-3beta inhibitor lithium or SB216763, mimicked IP-mediated angiogenesis and cardioprotection. Lithium- or SB216763- treated rats revealed accumulation of cytosolic and nuclear beta-catenin. This was followed by increased TCF/LEF transcriptional activity and the upregulation of VEGF, Bcl-2 and survivin mRNA expression accompanied by reduction of apoptotic cardiomyocytes and endothelial cells and increased capillary density after MI. The results of this study demonstrate, first time that inhibition of GSK-3beta followed by accumulation of beta-catenin in the cytosol and nucleus has potent anti-apoptotic and angiogenic effects after MI and that the PI3-kinase/GSK-3beta/beta-catenin signaling pathway plays an important role in IP.

Animals↗

PubMed2005

Resveratrol enhances neovascularization in the infarcted rat myocardium through the induction of thioredoxin-1, heme oxygenase-1 and vascular endothelial growth factor.

We have previously shown that resveratrol possesses cardioprotective effect, which may be attributed to its ability to (i) stimulate nitric oxide production and (ii) free radical scavenging activity. Since resveratrol is one of the major components of certain varieties of red grapes, these events may underlie the cardioprotective effects thought to be obtained from moderate red wine consumption. Here we report resveratrol enhanced myocardial angiogenesis both in vivo and in vitro by induction of vascular endothelial growth factor (VEGF), which was regulated by thioredoxin-1 (Trx-1) and heme oxygenase-1 (HO-1). Human coronary arteriolar endothelial cells exposed to resveratrol or Trx-1 on Matrigel demonstrated significantly accelerated tubular morphogenesis with induction of HO-1 and VEGF expression. This angiogenic response was repressed by tin-protoporphyrin IX (SnPP), an HO-1 inhibitor, along with downregulation of VEGF expression. However Trx-1 expression was not affected by SnPP. Again, rat neonatal cardiomyocytes treated with resveratrol significantly expressed Trx-1, HO-1 as well as VEGF. Rats were orally administered with resveratrol (1 mg/kg per day) for 14 days and then underwent permanent left anterior descending coronary artery (LAD) occlusion to document similar pro-angiogenic effect. Our results demonstrated that pretreatment with resveratrol markedly reduced infarct size 24 h after myocardial infarction (MI) and increased capillary density in the peri-infarct myocardium along with better left ventricular function 4 days after MI compared with vehicle-treated control. Concomitantly, resveratrol-treated myocardium after MI significantly induced Trx-1, HO-1 and VEGF expression. This effect was blocked by SnPP. Our findings suggest that resveratrol mediates cardioprotection and neovascularization through Trx-1-HO-1-VEGF pathway in rat ischemic myocardium.

Animals↗

PubMed2005

Resveratrol-mediated activation of cAMP response element-binding protein through adenosine A3 receptor by Akt-dependent and -independent pathways.

A recent study documented a role of adenosine A(3)-Akt-cAMP response element-binding protein (CREB) survival signaling in resveratrol preconditioning of the heart. In this study, we demonstrate that resveratrol-mediated CREB activation can also occur through an Akt-independent pathway. Isolated rat hearts were perfused for 15 min with Krebs-Henseleit bicarbonate (KHB) buffer containing resveratrol in the absence or presence of adenosine A(3) receptor blocker MRS-1191 [3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(+/-)-dihydropyridine-3,5-dicar-boxylate], phosphatidylinositol 3 (PI3)-kinase inhibitor LY294002 [2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride], mitogen-activated extracellular signal-regulated protein kinase inhibitor PD098059 [2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one], or a combination of LY294002 and PD098059. All hearts were subsequently subjected to 30-min ischemia followed by 2-h reperfusion. Cardioprotection was examined by determining infarct size, cardiomyocyte apoptosis, and ventricular recovery. Resveratrol phosphorylated both Akt and CREB that was blocked by MRS-1191, which also abolished cardioprotective abilities of resveratrol. LY294002 completely inhibited Akt phosphorylation but partially blocked the phosphorylation of CREB. Inhibition of PI3-kinase also partially blocked resveratrol's ability to precondition the heart. PD098059 partially blocked the phosphorylation of CREB and resveratrol-mediated cardioprotection. Preperfusing the hearts with LY294002 and PD098059 together completely abolished the phosphorylation of CREB, simultaneously inhibiting resveratrol-mediated cardioprotection. The results indicate that resveratrol preconditions the hearts through adenosine A(3) receptor signaling that triggers the phosphorylation of CREB through both Akt-dependent and -independent pathways, leading to cardioprotection.

Adenosine A3 Receptor Antagonists↗

PubMed2005

Cardioprotection with palm tocotrienol: antioxidant activity of tocotrienol is linked with its ability to stabilize proteasomes.

Tocotrienols, isomers of vitamin E, have been found to possess many health benefits. The present study was designed to determine whether tocotrienol has a direct cardioprotective role. Isolated rat hearts were perfused for 15 min with Krebs-Ringer bicarbonate buffer in the absence or presence of palm tocotrienol derived from the tocotrienol-rich fraction (0.035%) of palm oil (TRF). In another group of studies, the hearts were preperfused for 15 min in the presence of a c-Src inhibitor, 4-amino-5-(4-methylphenyl)-7-(t-butyl)-pyrazolo-3,4-d-pyrimidine (PPI). The hearts were then subjected to 30 min of global ischemia followed by 2 h of reperfusion. As expected, ischemia-reperfusion caused ventricular dysfunction, electrical rhythm disturbances, and increased myocardial infarct size. PPI or TRF could reverse the ischemia-reperfusion-mediated cardiac dysfunction. Ischemia-reperfusion also upregulated c-Src expression and phosphorylation. Although TRF only minimally affected c-Src expression, it significantly inhibited the phosphorylation of c-Src. Ischemia-reperfusion reduced 20S and 26S proteasome activities, an effect prevented by TRF pretreatment. PPI exerted a cardioprotective effect that is not mediated by the proteasome but, rather, through direct inhibition of c-Src. The results of this study support a role for c-Src in postischemic cardiac injury and dysfunction and demonstrate direct cardioprotective effects of TRF. The cardioprotective properties of TRF appear to be due to inhibition of c-Src activation and proteasome stabilization.

Animals↗

PubMed2005

Ischemic preconditioning-mediated cardioprotection is disrupted in heterozygous Flt-1 (VEGFR-1) knockout mice.

This study attempts to address an important clinical issue by identifying potential candidates of VEGF signaling through Flt-1 receptor that trigger angiogenic signal under ischemic stress. To determine the significance of VEGF-Flt-1 (VEGFR1) signaling in ischemic preconditioned (PC) myocardium, we used heterozygous Flt-1 knockout (KO) mice to dissect the pathway and identify candidate genes involved in VEGF signaling. DNA microarrays were employed to detect, characterize and distinguish altered myocardial gene expression by comparing between wild type (WT) CD-1 and heterozygous Flt-1 KO mice when exposed to ischemia (30 min) and reperfusion (2 h). Moreover, KO mice demonstrated reduced beneficial effects of PC when compared to the WT with PC. In the KO and WT mice, the % recovery of the left ventricular developed pressure and the maximum first derivative of the developed pressure after ischemia/reperfusion without PC were similar. However, when animals were subjected to PC, the left ventricular functional recovery throughout the reperfusion period was significantly lower in KO mice than in WT mice. These results indicate for the first time that in the heterozygous Flt-1 KO mice, PC is not as effective as that found in WT. This observation may be due to downregulation of several important genes such as growth-regulated oncogene 1 (Gro1), heat shock proteins (HSP), I kappa B kinase beta (IKK beta), colony-stimulating factor-1 (CSF-1) and annexin A7, suggesting the importance of VEGF-Flt-1 receptor signaling during PC.

Animals↗