Loss of cardioprotective effects of preinfarction angina in elderly but not in adult patients.
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Biomedical subjects
C Napoli
Publications and source records attributed to C Napoli.
Heart-targeted overexpression of caspase3 in mice increases infarct size and depresses cardiac function.
Up-regulation of proapoptotic genes has been reported in heart failure and myocardial infarction. To determine whether caspase genes can affect cardiac function, a transgenic mouse was generated. Cardiac tissue-specific overexpression of the proapoptotic gene Caspase3 was induced by using the rat promoter of alpha-myosin heavy chain, a model that may represent a unique tool for investigating new molecules and antiapoptotic therapeutic strategies. Cardiac-specific Caspase3 expression induced transient depression of cardiac function and abnormal nuclear and myofibrillar ultrastructural damage. When subjected to myocardial ischemia-reperfusion injury, Caspase3 transgenic mice showed increased infarct size and a pronounced susceptibility to die. In this report, we document an unexpected property of the proapoptotic gene caspase3 on cardiac contractility. Despite inducing ultrastructural damage, Caspase3 does not trigger a full apoptotic response in the cardiomyocyte. We also implicate Caspase3 in determining myocardial infarct size after ischemia-reperfusion injury, because its cardiomyocyte-specific overexpression increases infarct size.
Animals↗
c-myc activation in early coronary lesions in experimental hypercholesterolemia.
This study tested the hypothesis that c-Myc activation, an oxidation-sensitive transcription factor, and its binding partner Max occurs in coronary arteries of hypercholesterolemic (HC) pigs, and can be attenuated by chronic antioxidant intervention. Coronary arteries were isolated from normal, HC pigs, or HC supplemented with antioxidant vitamins (HC + vitamins). The expression of the c-Myc/Max complex, and its target genes GADD45 and p53, was studied in nonatherosclerotic, early lesions (LL), positively staining for oil-red-O, in adjacent lesion-prone regions (PL), and in healthy segments (HV). The expression of c-Myc and Max in HC was 2- to 3-fold greater in PL, and 4-fold in LL, compared to normal vessels (P < 0.01). The expression of GADD45 was down-regulated, and of p53 increased, in the same regions. These alterations were attenuated in the HC + vitamins. Thus, c-Myc activation is an early atherosclerosis, in both PL and LL coronary arterial regions, and can be blunted by chronic dietary antioxidant intervention.
Animals↗
Effects of nitric oxide-releasing aspirin versus aspirin on restenosis in hypercholesterolemic mice.
Restenosis is due to neointimal hyperplasia, which occurs in the coronary artery after percutaneous transluminal coronary angioplasty (PTCA). During restenosis, an impairment of nitric oxide (NO)-dependent pathways may occur. Concomitant hypercholesterolemia may exacerbate restenosis in patients undergoing PTCA. Here, we show that a NO-releasing aspirin derivative (NCX-4016) reduces the degree of restenosis after balloon angioplasty in low-density lipoprotein receptor-deficient mice and this effect is associated with reduced vascular smooth muscle cell (VSMC) proliferation and macrophage deposition at the site of injury. Drugs were administered following both therapeutic or preventive protocols. We demonstrate that NCX-4016 is effective both in prevention and treatment of restenosis in the presence of hypercholesterolemia. These data indicate that impairment of NO-dependent mechanisms may be involved in the development of restenosis in hypercholesterolemic mice. Although experimental models of restenosis may not reflect restenosis in humans in all details, we suggest that a NO-releasing aspirin derivative could be an effective drug in reducing restenosis following PTCA, especially in the presence of hypercholesterolemia and/or gastrointestinal damage.
Animals↗
Multiple role of reactive oxygen species in the arterial wall.
Increased oxidative stress plays an important role in vascular dysfunction and atherogenesis. Both systemic factors, such as hypercholesterolemia and hyperglycemia, and local factors, such as activation of macrophages and T cells, may contribute to oxidative stress. Oxidation of lipids in lipoproteins and cell membranes leads to functionally important modifications of proteins that affect their recognition by cell surface receptors and protein-protein interactions within the cell, including DNA binding. Oxidized LDL and extracellular oxidation modulate oxidation-sensitive signaling pathways, but it is not clear to what extent this results from receptor-mediated activation or from direct effects on the intracellular redox-balance. Extensive evidence indicates that reactive oxygen species (ROS) regulate gene expression by modulating a large number of transcription factors, including the nuclear transcription factor kappa B (NFkappaB), the peroxisome proliferator activated receptorgamma (PPARgamma), and pathways linked to apoptosis. It is also increasingly recognized that cell differentiation and proliferation, cytokine expression, and programmed cell death are determined by the interactions between oxidation-sensitive regulatory pathways previously thought to lead to distinct outcomes. Because hypercholesterolemia exerts pro-oxidant effects both intra- and extracellularly and because increased ROS formation affects vascular reactivity and atherogenesis by modulating multiple signaling pathways and transcriptional events, future investigations of its atherogenic mechanisms should place greater emphasis on the net effect of such modulation on the expression of a large spectrum of genes. One way of doing this will be by defining clusters of genes responding to hypercholesterolemic stimuli--or interventions with structurally unrelated antioxidants--in analogous ways, irrespective of what regulatory pathway they are controlled by. Microarray technologies that allow simultaneous assessment of large numbers of genes may provide a tool for this approach.
Animals↗
Spontaneous plaque rupture and secondary thrombosis in apolipoprotein E-deficient and LDL receptor-deficient mice.
Apolipoprotein E-deficient (apoE(-/-)) and LDL receptor-deficient (LDLR(-/-)) mice develop extensive atherosclerosis, but the occurrence of spontaneous plaque rupture and secondary thrombosis in these models has not been established. The goal of this study was to provide histological evidence of acute complications of atherosclerotic lesions in these mice and to assess their prevalence. Complications of atherosclerosis were initially studied in aortas of control mice which died during previous intervention studies. Coronary arteries and the aortic origin were then systematically assessed in serial sections through the heart of apoE(-/-) and LDLR(-/-) mice. Aortic plaque rupture and/or thrombi were seen in 3 of 82 untreated mice from past intervention studies. Screening of heart sections of 33 older apoE(-/-) mice (age 9-20 months) showed extensive atherosclerosis in one or more coronary arteries of 18 animals. In three coronary arteries, the presence of blood-filled channels within advanced atherosclerotic lesions suggested previous plaque disruption/thrombotic events followed by recanalization. In the aortic origin of the same mice, four deep plaque ruptures (or erosions reaching necrotic core areas) and a large thrombus originating from the core of a disrupted atherosclerotic lesion were observed. Although plaque ruptures/deep erosions were far less frequent than in human populations, these observations demonstrate that spontaneous plaque rupture and secondary thrombosis do occur in apoE(-/-) and LDLR(-/-) mice. These mice may therefore be suitable for studying factors contributing to thrombotic complications of atherosclerosis. However, the frequent absence of a clearly defined single fibrous cap in murine coronary lesions limits their usefulness as a model of fibrous cap rupture.
Animals↗
Nitric oxide and atherosclerosis.
Endothelial dysfunction has been shown in a wide range of vascular disorders including atherosclerosis and related diseases. Here, we examine and address the complex relationship among nitric oxide (NO)-mediated pathways and atherogenesis. In view of the numerous pathophysiological actions of NO, abnormalities could potentially occur at many sites: (a) impairment of membrane receptors in the arterial wall that interact with agonists or physiological stimuli capable of generating NO; (b) reduced concentrations or impaired utilization of l-arginine; (c) reduction in concentration or activity both of inducible and endothelial NO synthase; (d) impaired release of NO from the atherosclerotic damaged endothelium; (e) impaired NO diffusion from endothelium to vascular smooth muscle cells followed by decreased sensitivity to its vasodilator action; (f) local enhanced degradation of NO by increased generation of free radicals and/or oxidation-sensitive mechanisms; and (g) impaired interaction of NO with guanylate cyclase and consequent limitation of cyclic GMP production. Therefore, one target for new drugs should be the preservation or restoration of NO-mediated signaling pathways in arteries. Such novel therapeutic strategies may include administration of l-arginine/antioxidants and gene-transfer approaches.
Antioxidants↗
Hypercholesterolemia impairs myocardial perfusion and permeability: role of oxidative stress and endogenous scavenging activity.
OBJECTIVES: We intended to study the effect of hypercholesterolemia (HC) on myocardial perfusion and permeability response to increased cardiac demand. BACKGROUND: Hypercholesterolemia is associated with increased incidence of cardiac events and characterized by impaired coronary vascular function, possibly mediated partly through increased pro-oxidative conditions in plasma and tissue. However, it is yet unclear whether HC is also associated with impaired myocardial perfusion and vascular permeability responses in vivo. METHODS: For 12 weeks pigs were fed a normal, HC or HC diet supplemented daily with antioxidants (HC + AO, 100 IU/kg vitamin E and 1 g vitamin C). Myocardial perfusion and vascular permeability were measured in vivo using electron beam computed tomography before and after cardiac challenge with intravenous adenosine. Plasma and tissue oxidative status was determined ex vivo. RESULTS: Plasma cholesterol increased in all cholesterol-fed pigs but was associated with increased markers of oxidative stress only in HC pigs. Myocardial perfusion increased in response to adenosine in normal and HC + AO (+37 +/- 13% and +58 +/- 22%, respectively, p < 0.05 vs. baseline) but not in HC, whereas vascular permeability index increased only in HC pigs (+ 92 +/- 25%, p = 0.002). In HC animals, tissue endogenous oxygen radical scavengers and antioxidant vitamins were depleted and LDL oxidizability enhanced, but both were normalized in HC + AO pigs. Myocardial perfusion response was directly, and permeability inversely, associated with plasma and tissue vitamin concentrations. CONCLUSIONS: This study demonstrates that experimental HC is associated with blunted myocardial perfusion and increased vascular permeability responses in vivo to increased cardiac demand, which may be partly mediated by a shift in oxidative status.
Animals↗
Maternal hypercholesterolemia during pregnancy influences the later development of atherosclerosis: clinical and pathogenic implications.
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Adult↗
Mutated p21/WAF/CIP transgene overexpression reduces smooth muscle cell proliferation, macrophage deposition, oxidation-sensitive mechanisms, and restenosis in hypercholesterolemic apolipoprotein E knockout mice.
We have investigated whether by introducing a mutated p21 cyclin-dependent kinase inhibitor through a standard type 5 adenovirus (Ad), it would be possible to interfere with restenosis in hypercholesterolemic apolipoprotein E knockout mice. Restenosis is a clinically relevant, undesired effect of percutaneous transluminal coronary angioplasty (PTCA). A critical event underlying restenosis is smooth muscle cell (SMC) proliferation leading to neointimal formation and vessel reocclusion. Recent data demonstrated that it is possible to reduce restenosis by introducing various genes blocking the cell cycle through Ad vectors. Nonetheless, most experiments were conducted in the healthy carotid artery of rat, which is far from the condition of human disease. Therefore, we investigated whether antiproliferative or proapoptotic genes affect restenosis in a model of atherosclerosis closer to clinical settings. Ad-mutated(m)-p21WAF/CIP1 transgene overexpression induces a significant reduction of restenosis in hypercholesterolemic apolipoprotein E knockout mice subjected to injury of common carotid artery. This was associated with reduced SMC density and proliferation, macrophage deposition, and oxidation-sensitive mechanisms. Treatment with p21/WAF also enhanced TUNEL positivity of arterial cells. We show that in an experimental model of atherosclerosis, braking the cell proliferation through increased vascular apoptosis and reduced oxidation-sensitive signal transduction and macrophage accumulation can significantly ameliorate the deleterious effects of vascular injuries similar to those that occur during PTCA and related procedures.
Adenoviridae↗
Increased oxidative stress in experimental renovascular hypertension.
The pathophysiological mechanisms responsible for maintenance of chronic renovascular hypertension remain undefined. Excess angiotensin II generation may lead to release of reactive oxygen species and increased vasoconstrictor activity. To examine the potential involvement of oxidation-sensitive mechanisms in the pathophysiology of renovascular hypertension, blood samples were collected and renal blood flow measured with electron-beam computed tomography in pigs 5 and 10 weeks after induction of unilateral renal artery stenosis (n=7) or sham operation (n=7). Five weeks after procedure, plasma renin activity and mean arterial pressure were elevated in hypertensive pigs. Levels of prostaglandin F2alpha (PGF(2alpha))-isoprostanes, vasoconstrictors and markers of oxidative stress, also were significantly increased (157+/-21 versus 99+/-16 pg/mL; P<0.05) and correlated with both plasma renin activity (r=0.83) and arterial pressure (r=0.82). By 10 weeks, plasma renin activity returned to baseline but arterial pressure remained elevated (144+/-10 versus 115+/-5 mm Hg; P:<0.05). Isoprostane levels remained high and still correlated directly with the increase in arterial pressure (r=0.7) but not with plasma renin activity. Stenotic kidney blood flow was decreased at both studies. In shock-frozen cortical tissue, ex vivo endogenous intracellular radical scavengers were significantly decreased in both kidneys. The present study demonstrates, for the first time, that in early renovascular hypertension, an increase in plasma renin activity and arterial pressure is associated with increased systemic oxidative stress. When plasma renin activity later declines, PGF(2alpha)-isoprostanes remain elevated, possibly due to local activation or slow responses to angiotensin II, and may participate in sustenance of arterial pressure. Moreover, oxidation-sensitive mechanisms may influence ischemic and hypertensive parenchymal renal injury.
Animals↗
Combination of hypercholesterolemia and hypertension augments renal function abnormalities.
Hypercholesterolemia and hypertension are both risk factors for end-stage renal disease. This study was designed to examine whether their coexistence augmented impairment in renal function and redox status. Regional renal hemodynamics and function in response to vasoactive challenges with acetylcholine or sodium nitroprusside were quantified by using electron-beam computed tomography in pigs after 12 weeks of either a normal (n=10) or hypercholesterolemic (n=10) diet, renovascular hypertension (n=7), or combined hypercholesterolemia+hypertension (n=6). The hypercholesterolemic and hypercholesterolemic+hypertensive groups had significantly increased serum cholesterol levels, whereas in the hypertensive and hypercholesterolemic+hypertensive groups, mean arterial pressure was significantly elevated compared with the group fed a normal diet. Basal regional renal perfusion and glomerular filtration rates were similar among the groups. In response to acetylcholine, cortical perfusion increased in normal animals (15.6+/-4.7%, P=0.002) but not in hypercholesterolemic or hypertensive animals (8.0+/-7.4% and 8.2+/-5.9%, respectively; P>0.05). Moreover, in the hypercholesterolemic+hypertensive group, cortical perfusion response was further attenuated (2.5+/-4.8%, P=0.02) and significantly different from the group fed a normal diet (P<0.05). The response to sodium nitroprusside followed a similar pattern, and the impairment was augmented in the hypercholesterolemic+hypertensive group. The functional abnormalities in hypercholesterolemia or hypertension were associated with a decrease in systemic and/or renal tissue levels of oxygen radical scavengers that was again accentuated in hypercholesterolemia+hypertension. These results demonstrate that concurrent hypercholesterolemia and hypertension have a greater detrimental effect on renal perfusion responses compared with hypercholesterolemia or hypertension alone, associated with a marked pro-oxidant shift in redox status. These effects may potentially augment renal functional impairment and play a role in the initiation and progression of renal injury in hypertension and atherosclerosis.
Acetylcholine↗
Involvement of oxidation-sensitive mechanisms in the cardiovascular effects of hypercholesterolemia.
Hypercholesterolemia is a common clinical metabolic and/or genetic disorder that promotes functional and structural vascular wall injury. The underlying mechanisms for these deleterious effects involve a local inflammatory response and release of cytokines and growth factors. Consequent activation of oxidation-sensitive mechanisms in the arterial wall, modulation of intracellular signaling pathways, increased oxidation of low-density lipoprotein cholesterol, and quenching of nitric oxide can all impair the functions controlled by the vascular wall and lead to the development of atherosclerosis. This cascade represents a common pathological mechanism activated by various cardiovascular risk factors and may partly underlie synergism among them as well as the early pathogenesis of atherosclerosis. Antioxidant intervention and restoration of the bioavailability of nitric oxide have been shown to mitigate functional and structural arterial alterations and improve cardiovascular outcomes. Elucidation of the precise nature and role of early transductional signaling pathways and transcriptional events activated in hypercholesterolemia in children and adults, including mothers during pregnancy, and understanding their downstream effects responsible for atherogenesis may help in directing preventive and interventional measures against atherogenesis and vascular dysfunction.
Antioxidants↗
Maternal hypercholesterolemia enhances atherogenesis in normocholesterolemic rabbits, which is inhibited by antioxidant or lipid-lowering intervention during pregnancy: an experimental model of atherogenic mechanisms in human fetuses.
Maternal hypercholesterolemia during pregnancy is associated with a marked increase in aortic fatty streak formation in human fetuses and faster progression of atherosclerosis during normocholesterolemic childhood. However, the mechanisms responsible are unknown, and the contribution of genetic differences is difficult to assess in humans. The goal of this study was to determine whether maternal hypercholesterolemia per se may cause enhanced fatty streak formation in offspring and whether interventions during pregnancy can reduce it. During pregnancy, 1 group of New Zealand White rabbits was fed control chow and 8 groups were fed hypercholesterolemic diets Chol 1 (yielding plasma cholesterol of 153 mg/dL) or Chol 2 (yielding 359 mg/dL) without or with cholestyramine, vitamin E, or both. Offspring (n=15 to 25 per group) were killed at birth. Maternal hypercholesterolemia enhanced mean lesion size in the aorta of their offspring at birth from 44+/-18x10(3) micrometer(2) per section in controls to 85+/-26x10(3) in Chol 1 and 156+/-49x10(3) in Chol 2 groups (P<0.0001 for both). Cholestyramine or vitamin E treatment of mothers significantly reduced atherosclerosis at birth by up to 39% compared with controls on the same diet. Oxidized fatty acids and malondialdehyde in aortic atherosclerotic lesions and plasma were similarly affected by diets and treatment as atherosclerosis. Our results establish the causal role of hypercholesterolemia and peroxidation in fetal atherogenesis and demonstrate that both lipid-lowering and antioxidant interventions during pregnancy can reduce it. If it can be established that interventions in mothers also affect progression of lesions after birth, this may indicate a novel approach for the prevention of atherosclerosis.
Animals↗
Evidence for oxidative activation of c-Myc-dependent nuclear signaling in human coronary smooth muscle cells and in early lesions of Watanabe heritable hyperlipidemic rabbits: protective effects of vitamin E.
BACKGROUND: Oxidized LDL (oxLDL) promotes atherogenesis, and antioxidants reduce lesions in experimental models. OxLDL-mediated effects on c-Myc are poorly characterized, and those on c-Myc nuclear pathways are completely unknown. c-Myc stimulates smooth muscle cell (SMC) proliferation and could be involved in atherosclerosis. We investigated the early effects of oxLDL and alpha-tocopherol on c-Myc, its binding partner Max, and the carboxy-terminal domain-binding factors activator protein-2 and elongation 2 factor in human coronary SMCs. We also investigated whether 9-week treatment of Watanabe heritable hyperlipidemic (WHHL) rabbits with diet-enriched alpha-tocopherol reduces c-Myc expression and oxLDL in the left coronary artery. METHODS AND RESULTS: OxLDL enhanced c-Myc/Max expression and transcription by cotransfection assay and the nuclear activities of E2F and activator protein-2 by binding shift and supershift in coronary SMCs. alpha-Tocopherol significantly reduced these molecular events. Furthermore, alpha-tocopherol reduced early lesions, SMC density, and the immunohistochemical presence of c-Myc, which colocalized with oxLDL/foam cells in the coronaries of WHHL rabbits. CONCLUSIONS: We provide the first evidence that oxLDL and alpha-tocopherol may influence c-Myc activation and several c-Myc-dependent signaling pathways in human coronary SMCs. The observation that in vivo, an antioxidant reduces both c-Myc and oxLDL in early coronary lesions of rabbits is consistent with, but does not prove, the hypothesis that c-Myc-dependent factors activated by oxidative processes contribute to atherogenesis and coronary heart disease.
Animals↗
Modulation by alpha- and gamma-tocopherol and oxidized low-density lipoprotein of apoptotic signaling in human coronary smooth muscle cells.
Apoptosis may play an important role in atherogenesis. Oxidized low-density lipoprotein (oxLDL) promotes apoptosis in the arterial wall in addition to several other proatherogenic effects. Tocopherol supplements have been suggested to protect against coronary heart disease (CHD) in epidemiological studies. The effects of oxLDL and alpha- and gamma-tocopherol on apoptotic signaling pathways are poorly understood. Thus, the goal of the study was to investigate these pathways in the presence of copper-oxidized LDL and tocopherols in human coronary smooth muscle cells (SMC). We showed that oxLDL-mediated apoptosis, assessed by DNA fragmentation, terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) assay, and caspase activation stimulated several transcription factors and proapoptotic dynamic movements of the Bcl-2 family proteins through the mitogen-activated protein kinase (MAPK) and Jun kinase pathways. alpha-Tocopherol and gamma-tocopherol significantly reduced these molecular events and cell death effectors caspase-3 and -8. Under our experimental conditions, alpha-tocopherol was significantly more effective than gamma-tocopherol, and oxLDL-mediated apoptosis increased c-Jun, cyclic AMP-responsive element-binding, Ets-like element kinase-dependent 7, and activating transcription factor-2 proteins as well as nuclear activity of the activated protein-1 complex in human coronary SMC. Moreover, our results demonstrate that tocopherols may exert their antiatherogenic effects at least in part via reduction of the MAPK and JunK cascade together with a protective profile of apoptotic genes of the Bcl-2 family. These data are consistent with the beneficial effects of tocopherols on atherogenesis seen in experimental studies and on CHD in epidemiological surveys.
Adult↗
Protease-activated receptor-2 modulates myocardial ischemia-reperfusion injury in the rat heart.
Protease-activated receptor-2 (PAR-2) is a member of seven transmembrane domain G protein-coupled receptors activated by proteolytic cleavage whose better known member is the thrombin receptor. The pathophysiological role of PAR-2 remains poorly understood. Because PAR-2 is involved in inflammatory and injury response events, we investigated the role of PAR-2 in experimental myocardial ischemia-reperfusion injury. We show for the first time that PAR-2 activation protects against reperfusion-injury. After PAR-2-activating peptide (2AP) infusion, we found a significant recovery of myocardial function and decrease in oxidation at reflow. Indeed, the glutathione cycle (glutathione and oxidized glutathione) and lipid peroxidation analysis showed a reduced oxidative reperfusion-injury. Moreover, ischemic risk zone and creatine kinase release were decreased after PAR-2AP treatment. These events were coupled to elevation of PAR-2 and tumor necrosis factor alpha (TNFalpha) expression in both nuclear extracts and whole heart homogenates. The recovery of coronary flow was not reverted by L-nitroarginine methylester, indicating a NO-independent pathway for this effect. Genistein, a tyrosine kinase inhibitor, did not revert the PAR-2AP effect. During early reperfusion injury in vivo not only oxygen radicals are produced but also numerous proinflammatory mediators promoting neutrophil and monocyte targeting. In this context, we show that TNFalpha and PAR-2 are involved in signaling in pathophysiological conditions, such as myocardial ischemia-reperfusion. At the same time, because TNFalpha may exert pro-inflammatory actions and PAR-2 may constitute one of the first protective mechanisms that signals a primary inflammatory response, our data support the concept that this network may regulate body responses to tissue injury.
Animals↗
Ergonomics, gerontechnology and well-being in older patients with cardiovascular disease.
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