Dietary hempseed reduces platelet aggregation.
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Animals↗
Biomedical subjects
G N Pierce
Publications and source records attributed to G N Pierce.
Effect of dietary hempseed intake on cardiac ischemia-reperfusion injury.
Polyunsaturated fatty acids (PUFAs) have significant, cardioprotective effects against ischemia. Hempseed contains a high proportion of the PUFAs linoleic acid (LA) and alpha-linolenic acid (ALA), which may have opposing effects on postischemic heart performance. There are no reported data concerning the cardiovascular effects of dietary hempseed intake. A group of 40 male Sprague-Dawley rats were distributed evenly into four groups that were fed for 12 wk a normal rat chow supplemented with hempseed (5% and 10%), palm oil (1%), or a 10% partially delipidated hempseed that served as a control. Plasma ALA and gamma-linolenic acid levels were significantly elevated in the rats that were fed a 5% or 10% hempseed-supplemented diet, but in heart tissue only ALA levels were significantly elevated in the rats fed these diets compared with control. After the dietary interventions were completed, postischemic heart performance was evaluated by measuring developed tension, resting tension, the rates of tension development and relaxation, and the number of extrasystoles. Hearts from rats fed a hempseed-supplemented diet exhibited significantly better postischemic recovery of maximal contractile function and enhanced rates of tension development and relaxation during reperfusion than hearts from the other groups. These hearts, however, were not protected from the occurrence of extrasystoles, nor were the increases in resting tension altered during ischemia or reperfusion as a function of any dietary intervention. Our data demonstrate that dietary hempseed can provide significant cardioprotective effects during postischemic reperfusion. This appears to be due to its highly enriched PUFA content.
Animals↗
Effects of dietary flaxseed on vascular contractile function and atherosclerosis during prolonged hypercholesterolemia in rabbits.
Dietary flaxseed has significant anti-atherogenic effects. However, the limits of this action and its effects on vascular contractile function are not known. We evaluated the effects of flaxseed supplementation on atherosclerosis and vascular function under prolonged hypercholesterolemic conditions in New Zealand White rabbits assigned to one of four groups for 6, 8, or 16 wk of feeding: regular diet (RG), 10% flaxseed-supplemented diet (FX), 0.5% cholesterol-supplemented diet (CH), and 0.5% cholesterol- and 10% flaxseed-supplemented diet (CF). Cholesterol feeding resulted in elevated plasma cholesterol levels and the development of atherosclerosis. The CF group had significantly less atherosclerotic lesions in the aorta and carotid arteries after 6 and 8 wk than the CH animals. However, the anti-atherogenic effect of flaxseed supplementation was completely attenuated by 16 wk. Maximal tension induced in aortic rings either by KCl or norepinephrine was not impaired by dietary cholesterol until 16 wk. This functional impairment was not prevented by including flaxseed in the high-cholesterol diet. Aortic rings from the cholesterol-fed rabbits exhibited an impaired relaxation response to acetylcholine at all time points examined. Including flaxseed in the high-cholesterol diet completely normalized the relaxation response at 6 and 8 wk and partially restored it at 16 wk. No significant changes in the relaxation response induced by sodium nitroprusside were observed in any of the groups. In summary, dietary flaxseed is a valuable strategy to limit cholesterol-induced atherogenesis as well as abnormalities in endothelial-dependent vasorelaxation. However, these beneficial effects were attenuated during prolonged hypercholesterolemic conditions.
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Differential antioxidant properties of red wine in water soluble and lipid soluble peroxyl radical generating systems.
Red wine and its components have been shown to possess cardioprotective and anti-atherogenic effects. Additionally, red wine and many of its components like catechin, epicatechin, rutin, transresveratrol and quercetin possess antioxidant properties. Oxidized low density lipoprotein (LDL) is involved in the development of an atherosclerotic lesion. Red wine, therefore, may be anti-atherogenic because of its antioxidant effects on LDL modification. This study examined the antioxidant effects of catechin, epicatechin, rutin, transresveratrol, quercetin and Merlot wines on LDL oxidation. Merlot was chosen because although other red wines have been tested, limited information exists for this variety. Oxidation was carried out with AAPH (2,2'-Azo-bis(2-amidinopropane) dihydrochloride) and AMVN (2,2'-Azo-bis(2,4-dimethylvaleronitrile)), as water and lipid soluble peroxyl radical generating systems (FRGS), respectively. This allowed us to determine the lipophilic antioxidant characteristics of the wine and its components. Conjugated diene assays were used to measure LDL oxidation over 6 hrs. In an AAPH system, all polyphenolic compounds except transresveratrol displayed an antioxidant effect. LDL oxidation by AAPH was also inhibited by aliquots of Merlot wine. No antioxidant effects were observed in an AMVN environment except for a mild antioxidant effect by quercetin. Surprisingly, incubation of LDL with Merlot wine strongly protected against oxidation by AMVN. In summary, the five phenolic compounds displayed antioxidant effects in a water soluble free radical generating system, but only quercetin showed this in a lipid soluble one. However, red wine inhibited LDL oxidation by both water and lipid soluble free radical generating systems. Our data suggest, therefore, that red wines contain unidentified antioxidants that provide protection against LDL oxidation within a lipid soluble environment.
Amidines↗
Comparative analysis of the phenolic content of selected Chilean, Canadian and American Merlot red wines.
Flavonoids are a group of naturally occurring antioxidant compounds found in wine that are thought to have therapeutic importance in cardiovascular disease. The flavonoid content of red wines can differ as a function of the variety of wine examined. Since there is a paucity of data on the content of these antioxidants in Merlot wine, we used high performance liquid chromatography to identify and compare catechin, epicatechin, rutin, transresveratrol and quercetin levels in selected Merlot wines from Canada, Chile and the United States. Additionally, antioxidant content was correlated with the price of the wine. Catechin content was the most abundant when compared to the other four phenolic compounds. The concentrations of each compound in the Merlot wines also varied as a function of the country of origin. Catechin and transresveratrol occurred in significantly lower concentrations in Merlots from the United States. The lowest levels of rutin were observed in Canadian Merlots. Quercetin occurred at significantly higher levels in Chilean Merlots. Wine prices were inversely correlated with catechin concentration. Merlot wine represents a source of antioxidants that may have an impact on cardiovascular disease.
Antioxidants↗
Evidence for protection of nitrogenase from O(2) by colony structure in the aerobic diazotroph Gluconacetobacter diazotrophicus.
Gluconacetobacter diazotrophicus is an endophytic diazotroph of sugarcane which exhibits nitrogenase activity when growing in colonies on solid media. Nitrogenase activity of G. diazotrophicus colonies can adapt to changes in atmospheric partial pressure of oxygen (pO(2)). This paper investigates whether colony structure and the position of G. diazotrophicus cells in the colonies are components of the bacterium's ability to maintain nitrogenase activity at a variety of atmospheric pO(2) values. Colonies of G. diazotrophicus were grown on solid medium at atmospheric pO(2) of 2 and 20 kPa. Imaging of live, intact colonies by confocal laser scanning microscopy and of fixed, sectioned colonies by light microscopy revealed that at 2 kPa O(2) the uppermost bacteria in the colony were very near the upper surface of the colony, while the uppermost bacteria of colonies cultured at 20 kPa O(2) were positioned deeper in the mucilaginous matrix of the colony. Disruption of colony structure by physical manipulation or due to 'slumping' associated with colony development resulted in significant declines in nitrogenase activity. These results support the hypothesis that G. diazotrophicus utilizes the path-length of colony mucilage between the atmosphere and the bacteria to achieve a flux of O(2) that maintains aerobic respiration while not inhibiting nitrogenase activity.
Acetobacteraceae↗
Mg2+-dependent ATPase activity in cardiac myofibrils from the insulin-resistant JCR:LA-cp rat.
There is a great deal of information presently available documenting a cardiomyopathic condition in insulin-deficient models of diabetes. Less information is available documenting a similar status in non insulin-dependent models of diabetes. We have studied the functional integrity of the myofibrils isolated from hearts of JCR:LA rats. The JCR:LA rat is hyperinsulinemic, hyperlipidemic, glucose intolerant and obese. As such, it carries many of the characteristics found in humans with non insulin-dependent diabetes mellitus. These animals also have many indications of heart disease. However, it is not clear if the hearts suffer from vascular complications or are cardiomyopathic in nature. We examined Mg2+-dependent myofibrillar ATPase in hearts of JCR:LA-cp/cp rats and their corresponding control animals (+/?) and found no significant differences (P> 0.05). This is in striking contrast to the depression in this activity exhibited by cardiac myofibrils isolated from insulin-deficient models of diabetes. Our data demonstrate that myofibrillar functional integrity is normal in JCR:LA-cp rats and suggest that these hearts are not in a cardiomyopathic state. Insulin status may be critical in generating a cardiomyopathic condition in diabetes.
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Sodium-hydrogen exchange inhibition: pre-versus post-ischemic treatment.
Sodium-hydrogen exchange is involved in ischemia-reperfusion injury. Despite the strong research support for the use of sodium-hydrogen exchange blockers to protect the myocardium during ischemia-reperfusion, there is still controversy regarding the most effective time for drug delivery. Studies that initiate drug treatment immediately before or at reperfusion have given conflicting results. The conflict in results may be due to differences in the experimental design. Post-ischemic cardioprotection may be less than optimal due to the vascular permeability barrier or a limited collateral circulation. Increasing the drug dose or allowing more time for the drug to cross the vessel wall may overcome this limitation. Determining the correct dose and delivery protocol, therefore, will be critical for the generation of positive results in future clinical trials and will optimize the beneficial effects of sodium-hydrogen exchange inhibition in the treatment of reperfusion injury.
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Increase in nuclear calcium in smooth muscle cells exposed to oxidized low density lipoprotein.
Vascular smooth muscle cells respond with an increase in intracellular Ca2+ within seconds after exposure to oxidized low density lipoprotein (oxLDL). This has been suggested to represent a signaling response that may have implications for gene expression. If so, oxLDL may induce increases in nuclear Ca2+ in smooth muscle cells in response to oxLDL. Aortic smooth muscle cells were exposed to 100 microg/ml oxLDL. Large, rapid increases in [Ca2+]i were observed using fluo-3 as an indicator dye to detect intracellular Ca2+ on the stage of a confocal microscope. This was also confirmed using ratiometric imaging of indo signals. These elevations appeared to be localized to the nuclear region of the cell. DNA staining of the cells confirmed its localization to the nuclear/perinuclear region of the cell. Our data demonstrate that oxLDL induces a nuclear localized elevation in Ca2+i that may have important implications for nuclear function.
Adenosine Diphosphate↗
Growth-promoting effects of oxidized low density lipoprotein.
Oxidized low density lipoprotein (oxLDL) is a causative agent in the development and progression of atherosclerosis. It is believed to act in part by stimulating the proliferation of cells in the vessel wall. The present paper reviews the effects of oxLDL on proliferation in cultured vascular cells, as well as possible mechanisms by which oxLDL induces its mitogenic effect. These mechanisms include induction of cell cycle proteins, transcription factors, cytokines, growth factors and enzymes involved in mitogenesis.
Animals↗
Hydrogen peroxide inhibition of nuclear protein import is mediated by the mitogen-activated protein kinase, ERK2.
H(2)O(2) alters gene expression in many cell types. Alterations in nuclear import of transcription factors or similar key proteins may be responsible for these changes. To investigate this possibility, a cytosolic nuclear import cocktail was treated with varying ¿H(2)O(2) and used in import assays. H(2)O(2) caused a dose- and time-dependent inhibition of import at concentrations as low as 100 microM. Catalase reversed this effect. H(2)O(2) treatment of permeablized cells did not affect import, suggesting that H(2)O(2) was acting on a cytosolic factor. Treatment of import cocktail with two different free radical generating systems had no effect, but treatment of permeablized cells inhibited import, suggesting H(2)O(2) works via a distinct process from hydroxyl or superoxide radicals. Pretreatment of import cocktail with genistein reversed the effect of H(2)O(2) on import. Western blotting revealed that H(2)O(2) activated ERK2. The specific MEK1/2 inhibitor, PD98059, completely blocked the effects of H(2)O(2) on import. Activated ERK2 mimicked H(2)O(2)'s effect on import. Immunocytochemistry revealed that H(2)O(2) treatment of whole cells increased cytosolic Ran/TC4 levels, an effect reversible by catalase or PD98059. These data demonstrate that H(2)O(2) inhibits nuclear protein import and that this effect is mediated by mitogen-activated protein (MAP) kinase activation, possibly by altering Ran/TC4 function.
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Inhibition of Na(+)/H(+) exchange at the beginning of reperfusion is cardioprotective in isolated, beating adult cardiomyocytes.
Stimulation of Na(+)/H(+)exchange during ischemia-reperfusion results in cardiac damage. However, it is unclear whether the Na(+)/H(+)exchanger is active during the ischemic period or during reperfusion. Adult beating cardiomyocytes were exposed to an ischemia mimetic solution for 90 min and then reperfused with a normal solution for 30 min. 5-(N,N-dimethyl)-amiloride (DMA), a blocker of the Na(+)/H(+)exchanger, was administered during ischemia and the first 3 min of reperfusion or only during the first 3 min of reperfusion. Administration of DMA only upon reperfusion resulted in increased cell survival (81+/-1%, P<0.05) compared to using the drug during ischemia and reperfusion (63+/-3%) and in the absence of drug (60+/-1%). During ischemia, pH(i)was lower when DMA was present in the ischemic solution. The inhibition of the Na(+)/H(+)exchanger retarded the recovery of pH during reperfusion. The highest recovery of active cell shortening was observed when DMA was used at the beginning of reperfusion. The use of DMA also reduced the level of passive cell shortening during reperfusion, and when used at the beginning of reperfusion significantly increased the recovery of Ca(2+)transients. Our results demonstrate that the exchanger is primarily active during reperfusion and that inhibition of the exchanger solely at this time has a strong cardioprotective effect.
Amiloride↗
Cell cycle proteins and atherosclerosis.
Progression of the eukaryotic cell through the cell cycle to induce cell proliferation is a fundamental event in developmental growth processes. Specific cell cycle proteins are critical for either inducing or suppressing the cell cycle. These proteins, therefore, have been found to be key players in regulating cell proliferation in diseases like cancer and atherosclerosis. The present manuscript reviews the process of cell proliferation in atherosclerosis and the data that have implicated the various cell cycle proteins in restenotic and atherosclerotic vascular disease.
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Overexpression of SERCA2 Atpase in vascular smooth muscle cells treated with oxidized low density lipoprotein.
Oxidized low density lipoprotein (oxLDL) has been identified as a potentially important atherogenic factor. Atherosclerosis is characterized by the accumulation of lipid and calcium in the vascular wall. OxLDL plays a significant role in altering calcium homeostasis within different cell types. In our previous study, chronic treatment of vascular smooth muscle cells (VSMC) with oxLDL depressed Ca2+(i) homeostasis and altered two Ca2+ release mechanisms in these cells (IP3 and ryanodine sensitive channels). The purpose of the present study was to further define the effects of chronic treatment with oxLDL on the smooth muscle sarcoplasmic reticulum (SR) Ca2+ pump. One of the primary Ca2+ uptake mechanisms in VSMC is through the SERCA2 ATPase calcium pump in the sarcoplasmic reticulum. VSMC were chronically treated with 0.005-0.1 mg/ml oxLDL for up to 6 days in culture. Cells treated with oxLDL showed a significant increase in the total SERCA2 ATPase content. These changes were observed on both Western blot and immunocytochemical analysis. This increase in SERCA2 ATPase is in striking contrast to a significant decrease in the density of IP3 and ryanodine receptors in VSMC as the result of chronic treatment with oxLDL. This response may suggest a specific adaptive mechanism that the pump undergoes to attempt to maintain Ca2+ homeostasis in VSMC chronically exposed to atherogenic oxLDL.
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Chlamydia pneumoniae infection significantly exacerbates aortic atherosclerosis in an LDLR-/- mouse model within six months.
We have previously shown that infection with the C. pneumoniae AR39 strain once monthly for 9 consecutive months significantly exacerbated atherosclerosis in mice with LDL receptor deficiency (LDLR-/-) in the presence of a high cholesterol diet. To further optimize the LDLR-/- mouse model for studying the mechanisms of C. pneumoniae atherogenesis, we have tested a different infection protocol with intranasal inoculation twice monthly for 6 consecutive months in the present study. We found that C. pneumoniae infection for 6 months was sufficient to produce a 130%, significantly greater exacerbation of aortic atherosclerosis in LDLR-/- mice in the presence of a high cholesterol diet. Mice receiving a high cholesterol diet alone displayed a lesion area index of 18.2 +/- 6.1 (S.D.) while mice treated with both the high cholesterol diet and C. pneumoniae infection had a lesion area index of 41.8 +/- 15.2 (S.D.). However, the chlamydial infection did not significantly alter the mouse serum total cholesterol or the LDL levels induced by the high cholesterol diet. This study not only confirms our previous findings that C. pneumoniae infection can exacerbate aortic atherosclerosis lesion in the LDLR-/- mice, but also further optimizes the LDLR-/- mouse model for future mechanism studies.
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Altered cardiac Na(+)/H(+) exchange in phospholipase D-treated sarcolemmal vesicles.
Cardiac sarcolemmal Na(+)/H(+) exchange is critical for the regulation of intracellular pH, and its activity contributes to ischemia-reperfusion injury. It has been suggested that the membrane phospholipid environment does not modulate Na(+)/H(+) exchange. The present study was carried out to determine the effects on Na(+)/H(+) exchange of modifying the endogenous membrane phospholipids through the addition of exogenous phospholipase D. Incubation of 0.825 U of phospholipase D with 1 mg of porcine cardiac sarcolemmal vesicles hydrolyzed 34 +/- 2% of the sarcolemmal phosphatidylcholine and increased phosphatidic acid 10.2 +/- 0.5-fold. Treatment of vesicles with phospholipase D resulted in a 46 +/- 2% inhibition of Na(+)/H(+) exchange. Na(+)/H(+) exchange was measured as a function of reaction time, extravesicular pH, and extravesicular Na(+). All of these parameters of Na(+)/H(+) exchange were inhibited following phospholipase D treatment compared with untreated controls. Passive efflux of Na(+) was unaffected. Treatment of sarcolemmal vesicles with phospholipase C had no effect on Na(+)/H(+) exchange. We conclude that phospholipase D-induced changes in the cardiac sarcolemmal membrane phospholipid environment alter Na(+)/H(+) exchange.
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Lesions in ryanodine channels in smooth muscle cells exposed to oxidized low density lipoprotein.
The purpose of the present investigation was to investigate the subcellular basis responsible for the loss of vasoreactivity in atherosclerotic vessels. We have chosen to focus on the potential of oxidized low density lipoprotein (oxLDL), an important atherogenic agent, to alter sarcoplasmic reticulum (SR) structure and function. Vascular smooth muscle cells (VSMCs) were exposed for 1 to 6 days to low concentrations of minimally oxidized LDL. ATP was used to probe SR function in VSMCs. ATP can increase [Ca(2+)](i) in control VSMCs because of a release of Ca(2+) from the SR. However, after chronic exposure to oxLDL, cells lose their ability to increase [Ca(2+)](i) in response to ATP. These cells also exhibit a depressed rise in [Ca(2+)](i) after exposure to ryanodine. These effects were associated with a decreased immunoreactivity for the ryanodine-sensitive Ca(2+)-release channels in the SR of oxLDL-treated cells. Immunohistochemical analysis of aortic sections obtained from rabbits fed a cholesterol-supplemented diet revealed a significant decrease in the immunoreactivity for ryanodine channels in the plaque and in the medial layer underlying the plaque. In summary, our data identify oxLDL as a component within the atherosclerotic milieu capable of inducing a decrease in smooth muscle ryanodine channel density. This alteration is associated with a significant defect in the ability of the SR within the smooth muscle cell to regulate Ca(2+). These lesions may contribute to the altered vasoreactivity exhibited by atherosclerotic vessels.
Adenosine Triphosphate↗
Chronic exposure of smooth muscle cells to minimally oxidized LDL results in depressed inositol 1,4,5-trisphosphate receptor density and Ca(2+) transients.
Oxidized LDL (oxLDL) (0.1 mg/mL) increased [Ca(2+)](i) in vascular smooth muscle cells (VSMCs) within 5 to 10 seconds of incubation. This increase was mediated via an inositol 1,4,5-trisphosphate (IP(3))-dependent release of Ca(2+) from the sarcoplasmic reticulum. However, atherosclerosis is a gradual process in which VSMCs are more likely exposed to low concentrations of oxLDL over extended periods rather than acute exposures. It is very possible, therefore, that lower [oxLDL] and longer exposure times may induce a very different response with regard to regulation of [Ca(2+)](i). VSMCs were incubated with 4- to 100-fold lower [oxLDL] for up to 6 days. The conditions were not cytotoxic. Basal [Ca(2+)](i) was not altered. Surprisingly, however, after chronic exposure to oxLDL, a brief addition of oxLDL (0.1 mg/mL) or norepinephrine failed to elicit the expected rise in Ca(2+)(i). Because the acute effects of oxLDL on control cells were mediated through an IP(3)-dependent pathway, we investigated the integrity of the VSMC IP(3) receptors. Immunocytochemical analysis and Western blots revealed a depression in the density of IP(3) receptors after chronic exposure of VSMCs to oxLDL. These changes in IP(3) receptors have significance under atherosclerotic conditions as well. Immunocytochemical analysis revealed a decrease in IP(3) receptor density in the medial layer under atherosclerotic plaques in situ. Our data, therefore, demonstrate a striking difference between the acute and chronic effects of oxLDL on VSMC calcium. Whereas acute exposure to oxLDL stimulates [Ca(2+)](i), chronic exposure results in depressed Ca(2+) transients, apparently through a decrease in IP(3) receptor density. These changes have functional implications for the atherosclerotic vessel in vivo, and our data implicates oxLDL in this process.
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