Enhanced atherosclerosis and kidney dysfunction in eNOS–/–Apoe–/– mice are ameliorated by enalapril treatment

Knowles, Joshua W.; Reddick, Robert L.; Jennette, J. Charles; Shesely, Edward G.; Smithies, Oliver; Maeda, Nobuyo

doi:10.1172/jci8376

Cited by 278 publications

(210 citation statements)

References 51 publications

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“…5,6 ApoE/eNOS DKO mice develop atherosclerosis at an accelerated rate compared with apoE KO mice, confirming that eNOS protects against atherogenesis. However, apoE/eNOS DKO mice are hypertensive, with mean arterial blood pressures similar to eNOS KO mice.…”

Section: Discussionmentioning

confidence: 80%

“…Despite important differences between their study and our previous one, 5 in both cases, apoE/eNOS DKO mice developed significantly greater atherosclerotic lesion areas than control apoE KO mice, confirming a role for eNOS in the suppression of atherogenesis. Knowles et al 6 found that enalapril lowered the blood pressure of apoE/eNOS DKO mice and reduced the development of lesions. 6 This indicates that the mechanism of enalapril action does not depend on eNOS.…”

Section: Discussionmentioning

confidence: 99%

“…5,6 We previously found that apoE/eNOS double knockout (DKO) mice develop increased aortic lesions after 16 weeks of a Westerntype diet; these lesions are also associated with distal coronary artery disease and left ventricular dysfunction. Furthermore, male apoE/eNOS DKO mice developed abdominal aortic aneurysm and aortic dissection.…”

mentioning

confidence: 99%

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Hypertension Does Not Account for the Accelerated Atherosclerosis and Development of Aneurysms in Male Apolipoprotein E/Endothelial Nitric Oxide Synthase Double Knockout Mice

et al. 2001

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Background-Apolipoprotein E (apoE)/endothelial nitric oxide synthase (eNOS) double knockout (DKO) mice demonstrate accelerated atherosclerosis and develop abdominal aortic aneurysms and aortic dissection, suggesting a role for eNOS in suppressing atherogenesis. To test whether accelerated atherosclerosis and aortic aneurysms were due to hypertension, we administered hydralazine to male apoE/eNOS DKO mice to reduce blood pressure. Methods and Results-Male apoE/eNOS DKO mice were treated with hydralazine in their drinking water (250 mg/L) using a dose that lowers the blood pressure to levels seen in apoE KO mice. The mice were fed a Western-type diet for 16 weeks, and lesion formation was assessed by inspection of the vessel and staining with Sudan IV. Hydralazinetreated, normotensive male apoE/eNOS DKO mice developed increased aortic lesion areas (30.0Ϯ2.8%, nϭ11) compared with male apoE KO mice (14.6Ϯ0.8%, nϭ7). The extent of lesion formation was not significantly different from male apoE/eNOS DKO mice that were not given hydralazine (28.3Ϯ3.1%, nϭ9). Four of 11 hydralazine-treated male apoE/eNOS DKO mice developed abdominal aortic aneurysms. Conclusions-Hypertension is not required for the accelerated atherosclerosis seen in apoE/eNOS DKO animals, and control of hypertension during a 16-week period does not prevent aortic aneurysm formation.

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Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

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Hypertension Does Not Account for the Accelerated Atherosclerosis and Development of Aneurysms in Male Apolipoprotein E/Endothelial Nitric Oxide Synthase Double Knockout Mice

et al. 2001

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“…It is, therefore, not surprising that loss of endothelial NO function initiates and accelerates atherogenesis, as demonstrated by various experiments with animal models [5,6]. Although our understanding of biochemical regulation of endothelial NO bioactivity has remarkably advanced on various levels of eNOS gene expression-eNOS enzymatic activity to degradation of NO [7]-no single mechanism can fully explain endothelial dysfunction in atherosclerosis.…”

Section: Introductionmentioning

confidence: 99%

Endothelial arginase: A new target in atherosclerosis

Yang

Ming

2006

Current Science Inc

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“…Genetic deficiency of iNOS in itself does not change atherosclerotic lesion size in diet-induced atherosclerosis [122]. In contrast, all studies but one using the apolipoprotein E-deficient (apoE −/−) mouse model of atherosclerosis have shown decreased atherogenesis in iNOS/apoE double knockout animals [23,33,85,93,112]. Perivascular cuffing of the carotid artery in iNOS knockout mouse is also associated with decreased neointima formation indicating a contribution of iNOS to the development of vascular injury [4,26].…”

Section: The Essential Role Of Inos During Vascular Injury: Good or Bmentioning

confidence: 99%

Regulation of smooth muscle by inducible nitric oxide synthase and NADPH oxidase in vascular proliferative diseases

Ginnan

Guikema

Halligan

et al. 2008

Free Radical Biology and Medicine

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Inflammation plays a critical role in promoting smooth muscle migration and proliferation during vascular diseases such as post-angioplasty restenosis and atherosclerosis. Another common feature of many vascular diseases is the contribution of reactive oxygen (ROS) and nitrogen (RNS) species to vascular injury. Primary sources of ROS and RNS in smooth muscle are several isoforms of NADPH oxidase (Nox) and the cytokine-regulated inducible nitric oxide (NO) synthase (iNOS). One important example of the interaction between NO and ROS is the reaction of NO with superoxide to yield peroxynitrite, which may contribute to the pathogenesis of hypertension. In this review, we discuss the literature that supports an alternate possibility: Nox-derived ROS modulate NO bioavailability by altering the expression of iNOS. We highlight data showing co-expression of iNOS and Nox in vascular smooth muscle and demonstrating the functional consequences of iNOS and Nox during vascular injury. We describe the relevant literature demonstrating that the mitogen activated protein kinases (MAP kinases) are important modulators of pro-inflammatory cytokinedependent expression of iNOS. A central hypothesis discussed is that ROS-dependent regulation of the serine/threonine kinase protein kinase Cδ (PKCδ) is essential to understanding how Nox may regulate signaling pathways leading to iNOS expression. Overall, the integration of non-phagocytic NADPHoxidase with cytokine signaling in general and in vascular smooth muscle in particular is poorly understood and merit further investigation.

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Enhanced atherosclerosis and kidney dysfunction in eNOS–/–Apoe–/– mice are ameliorated by enalapril treatment

Cited by 278 publications

References 51 publications

Hypertension Does Not Account for the Accelerated Atherosclerosis and Development of Aneurysms in Male Apolipoprotein E/Endothelial Nitric Oxide Synthase Double Knockout Mice

Hypertension Does Not Account for the Accelerated Atherosclerosis and Development of Aneurysms in Male Apolipoprotein E/Endothelial Nitric Oxide Synthase Double Knockout Mice

Endothelial arginase: A new target in atherosclerosis

Regulation of smooth muscle by inducible nitric oxide synthase and NADPH oxidase in vascular proliferative diseases

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