Hypercholesterolemia impairs myocardial perfusion and permeability: role of oxidative stress and endogenous scavenging activity

Rodriguez-Porcel, Martin; Lerman, Amir; Best, Patricia J.M.; Krier, James D.; Napoli, Claudio; Lerman, Lilach O.

doi:10.1016/s0735-1097(00)01139-6

Cited by 78 publications

(105 citation statements)

References 44 publications

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“…Risk of CHD increases progressively with higher levels of low-density lipoprotein (LDL) cholesterol while higher levels of high-density lipoprotein (HDL) cholesterol reduces the risk significantly. Furthermore, CHD is also found to be associated with coronary endothelial dysfunction and myocardial perfusion abnormalities [15]. Several clinical trials have demonstrated that statin therapy is effective for both the primary and secondary prevention of coronary artery diseases.…”

Section: Discussionmentioning

confidence: 99%

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

Penumathsa

Thirunavukkarasu

Koneru

et al. 2007

Journal of Molecular and Cellular Cardiology

152

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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 are more cardioprotective than individual treatment groups in ischemic rat heart model. The rats were fed rats with 2% high cholesterol diet and after 8 weeks of high cholesterol diet the animals were treated with statin (1mg/kg bw/day) and resveratrol (20mg/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) 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 size 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 one 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 β-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, antihyperlipidemic and anti-apoptotic effects and long term effects may be caused by increased neovascularization of the MI zone leading to less ventricular remodeling.

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Section: Discussionmentioning

confidence: 99%

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

Penumathsa

Thirunavukkarasu

Koneru

et al. 2007

Journal of Molecular and Cellular Cardiology

152

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“…Upregulation of VEGF and VEGFR-2 in the vessel wall could account for the increased vascular permeability [23] and enhanced vasa vasorum neovascularization observed in experimental models of hypercholesterolemia [24]. Although the mechanism by which hypercholesterolemia may induce VEGF upregulation in the vessel wall remains unclear, possible pathophysiological stimuli include hypoxia [14], oxidative stress [3] and low NO bioavailability [4].…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, VEGF upregulation has been proposed to be a non-specific stress-induced vascular response in the adult organism [25], or to constitute a vascular homeostatic mechanism for compensating endothelial dysfunction [1]. Independently of the mechanism responsible, sustained vascular VEGF overexpression could contribute to the atherosclerotic process by favoring lipoprotein infiltration through increased vascular permeability [23], inflammation [26] and angiogenesis [8]. The anti-atherosclerotic effect of the angiogenesis inhibitors endostatin and TNP-470 in the apoE−/− [10] would support this hypothesis.…”

Section: Discussionmentioning

confidence: 99%

Vitamins C and E downregulate vascular VEGF and VEGFR-2 expression in apolipoprotein-E-deficient mice

et al. 2003

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Anti-angiogenic therapy reduces both plaque growth and intimal neovascularization in apolipoprotein-E-deficient mice (apoE−/−). Vascular endothelial growth factor (VEGF) has been suggested as playing a role in the development of atherosclerosis. We examined the hypothesis that VEGF and VEGF receptor-2 (VEGFR-2) expression is upregulated in apoE−/− and, since it could be driven by oxidative stress, tested whether dietary supplementation with vitamins C and E could downregulate it. Two-month-old apoE−/− received vitamin C combined with ␣-or ␤-tocopherol for 4 weeks. Aortic VEGF and VEGFR-2 expression were measured by RT-qPCR and western blot.ApoE−/− showed significantly higher expression of aortic VEGF and VEGFR-2 mRNA (P < 0.001) and protein (P < 0.001) than wild-type mice, as well as increased plasma VEGF (P < 0.001). Vitamin C and ␣-tocopherol significantly reduced aortic VEGF and VEGFR-2 expression in apoE−/− (P < 0.001), circulating VEGF (P < 0.01) and plasma lipid peroxidation (P < 0.01). apoE−/− receiving vitamin C and ␤-tocopherol showed diminished lipid peroxidation and VEGFR-2, but only partial reduction of VEGF expression.These data demonstrate that augmented VEGF and VEGFR-2 expression in apoE−/− vasculature can be downregulated by vitamins C and E, at least partially through oxidative stress reduction. This novel mechanism could contribute to explaining the beneficial effects of antioxidant vitamins in experimental atherosclerosis.

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“…This scanner has been proven to be an accurate (4), reproducible (25), and minimally invasive (27) tool for in vivo study of microcirculatory functional parameters, such as myocardial perfusion and permeability indices (27,29,30,32). The technical properties of the EBCT scanner (model C-150; Imatron, South San Francisco, CA) have been described in detail elsewhere (27,32,33). Animals were positioned supine in the EBCT gantry so that the heart was centered in the imaging field and fixed in the position for the subsequent studies.…”

Section: Methodsmentioning

confidence: 99%

“…However, it has been shown that myocardial microvascular permeability can change under various pathologic and metabolic circumstances such as diabetes mellitus (24,41), hypercholesterolemia (32), hypertension (31), and acute myocardial ischemia followed by reperfusion (29). Embolization of microscopic plaque debris into the distal coronary bed during coronary interventions is a common and frequent event (9,10,35) that might be associated with microinfarctions and with adverse clinical outcome (7,10).…”

mentioning

confidence: 99%

Relationship between surface area of nonperfused myocardium and extravascular extraction of contrast agent following coronary microembolization

Malyar

Lerman

Gössl

et al. 2011

American Journal of Physiology-Regulatory, Integrative and Comp

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Malyar NM, Lerman LO, Gössl M, Beighley PE, Ritman EL. Relationship between surface area of nonperfused myocardium and extravascular extraction of contrast agent following coronary microembolization. Am J Physiol Regul Integr Comp Physiol 301: R430-R437, 2011. First published May 4, 2011 doi:10.1152/ajpregu.00428.2010.-Myocardial microvascular permeability and coronary sinus concentration of muscle metabolites have been shown to increase after myocardial ischemia due to epicardial coronary artery occlusion and reperfusion. However, their association with coronary microembolization is not well defined. This study tested the hypothesis that acute coronary microembolization increases microvascular permeability in the porcine heart. The left anterior descending perfusion territories of 34 anesthetized pigs (32 Ϯ 3 kg) were embolized with equal volumes of microspheres of one of three diameters (10, 30, or 100 m) and at three different doses for each size. Electron beam computed tomography (EBCT) was used to assess in vivo, microvascular extraction of a nonionic contrast agent (an index of microvascular permeability) before and after microembolization with microspheres at baseline and during adenosine infusion. A high-resolution three-dimensional microcomputed tomography (micro-CT) scanner was subsequently used to obtain ex vivo, the volume and corresponding surface area of the embolized myocardial islands within the perfusion territories of the microembolized coronary artery. EBCT-derived microvascular extraction of contrast agent increased within minutes after coronary microembolization (P Ͻ 0.001 vs. baseline and vs. control values). The increase in coronary microvascular permeability was highly correlated to the micro-CT-derived total surface area of the nonperfused myocardium (r ϭ 0.83, P Ͻ 0.001). In conclusion, myocardial extravascular accumulation of contrast agent is markedly increased after coronary microembolization and its magnitude is in proportion to the surface area of the interface between the nonperfused and perfused territories. microspheres; EBCT; micro-CT; microvascular permeability A BALANCE BETWEEN DELIVERY of vital nutrients and removal of waste products from the myocardium is pivotal for maintaining the physiological contractile function of the myocytes and for the coordinated electrical conductance along the cells' membranes. However, it has been shown that myocardial microvascular permeability can change under various pathologic and metabolic circumstances such as diabetes mellitus (24, 41), hypercholesterolemia (32), hypertension (31), and acute myocardial ischemia followed by reperfusion (29). Embolization of microscopic plaque debris into the distal coronary bed during coronary interventions is a common and frequent event (9, 10, 35) that might be associated with microinfarctions and with adverse clinical outcome (7, 10).We have previously demonstrated that experimental coronary microembolization leads to a decrease in regional myocardial contractility that is proportional to the surface...

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Hypercholesterolemia impairs myocardial perfusion and permeability: role of oxidative stress and endogenous scavenging activity

Abstract: 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.

Cited by 78 publications

References 44 publications

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

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

Vitamins C and E downregulate vascular VEGF and VEGFR-2 expression in apolipoprotein-E-deficient mice

Relationship between surface area of nonperfused myocardium and extravascular extraction of contrast agent following coronary microembolization

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