Hemodynamic changes in apolipoprotein E-knockout mice

Hartley, Craig J.; Reddy, Anilkumar K.; Madala, Sridhar; Martin-McNulty, Baby; Vergona, Ronald; Sullivan, M.; Halks-Miller, Meredith; Taffet, George E.; Michael, Lloyd H.; Entman, Mark L.; Wang, Yi Xin

doi:10.1152/ajpheart.2000.279.5.h2326

Cited by 131 publications

(135 citation statements)

References 31 publications

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“…Although the atherosclerotic lesions are progressive and may become severe, their functional effect on blood flow and physiology is largely unknown. Cardiovascular reserve relevant to exercise performance is reduced (Niebauer et al, 1999), and we have previously shown a 55% increase in aortic and mitral flow velocities and a 59% increase in heart-weight to body-weight ratio at 1 year of age (Hartley et al, 2000) consistent with volume overload hypertrophy. However, the effect and significance of systemic and coronary arterial lesions and of the cardiac hypertrophy on coronary blood flow and coronary flow reserve in ApoE −/− mice is unknown.…”

Section: Introductionmentioning

confidence: 54%

“…Our findings in mice are in substantial agreement with the findings in rats and in man that age and baseline velocity are the major factors determining H/B in the absence of coronary stenoses. Conditions which increase baseline cardiac work such as pressure (Rockman et al, 1993) or volume (Hartley et al, 2000) overload would be expected to decrease coronary reserve in mice as they do in man (Marcus et al, 1982). However, it remains unclear whether the lower baseline velocity in Old versus Young mice is due to reduced demand at rest or to differential sensitivity to isoflurane.…”

Section: H/b In Mice Versus Manmentioning

confidence: 99%

“…This encouraged us to test the feasibility of using a smaller and more focused Doppler probe to measure coronary flow velocity and to estimate reserve in a mouse model of atherosclerosis (Plump et al, 1992;Wang, 2005) where we hypothesized that the presence of lesions in the left main coronary artery coupled with volume overload hypertrophy (Hartley et al, 2000) would reduce coronary flow reserve. Thus, we report here a noninvasive method using Doppler ultrasound (Hartley et al, 2000) to measure left main coronary flow velocity and the response to low and high levels of inhaled isoflurane in young and old wildtype, and old (age-matched) ApoE −/− mice (Bernard et al, 1992;Crystal, 1996). We use the response to isoflurane to document systematic differences in baseline and hyperemic coronary flow velocity among the groups and to demonstrate large variations in baseline and hyperemic coronary artery velocities in ApoE −/− mice likely due to the presence of stenotic coronary artery lesions.…”

Section: Introductionmentioning

confidence: 99%

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Effects of Isoflurane on Coronary Blood Flow Velocity in Young, Old and ApoE−/− Mice Measured by Doppler Ultrasound

Hartley

Reddy

Madala

et al. 2007

Ultrasound in Medicine & Biology

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The commonly used anesthetic agent, isoflurane (ISO), is a potent coronary vasodilator which could potentially be used in the assessment of coronary reserve, but its effects on coronary blood flow in mice are unknown. Coronary reserve is reduced by age, coronary artery disease, and other cardiac pathologies in man, and some of these conditions can now be modeled in mice. Accordingly, we used Doppler ultrasound to measure coronary flow velocity in mice anesthetized at low (1%) and at high (2.5%) levels of ISO to generate baseline (B) and elevated hyperemic (H) and Y and between A and O were significant (P < 0.01), while the differences in hyperemic velocities were not (P > 0.05). H/B was higher in old mice due to decreased baseline flow rather than increased hyperemic flow velocity. In contrast ApoE −/− mice have increased baseline and hyperemic velocities perhaps due to coronary lesions. The differences in baseline velocities between young and old mice could be due to age-related changes in basal metabolism or to differential sensitivity to isoflurane. We conclude that Doppler ultrasound combined with coronary vasodilation via isoflurane could provide a convenient and noninvasive method to estimate coronary reserve in mice, but also that care must be taken when assessing coronary flow in mice under isoflurane anesthesia because of its potent coronary vasodilator properties.

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Section: Introductionmentioning

confidence: 54%

Section: H/b In Mice Versus Manmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effects of Isoflurane on Coronary Blood Flow Velocity in Young, Old and ApoE−/− Mice Measured by Doppler Ultrasound

Hartley

Reddy

Madala

et al. 2007

Ultrasound in Medicine & Biology

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“…This type of consideration is particularly important when interpreting traits of apoE-/-mice that are quantitative and not directly explainable by the function of apoE in lipid metabolism. These include blood pressure (9), kidney damage (10), behavior (11), and susceptibility to infections (12,13). The observed phenotypes could be secondary to hyperlipidemia and/or atherosclerosis induced by lack of apoE, or the consequence of yet-to-be defined functions of apoE.…”

mentioning

confidence: 99%

Anatomical differences and atherosclerosis in apolipoprotein E-deficient mice with 129/SvEv and C57BL/6 genetic backgrounds

et al. 2007

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There are well-known genetic background effects on atherosclerosis susceptibility in mice. To study the basis of these effects, we have generated the apolipoprotein E-null mutation in mouse embryonic stem cells of 129/SvEv origin, maintained it in the inbred strain (129-apoE), and compared these mice with those previously made in strain 129/Ola and backcrossed to a C57BL/6 genetic background (B6-apoE). Plasma cholesterol and triglyceride levels in the apoE-129 mice are twice the levels in apoE-B6, and both VLDL/chylomicron remnants and HDL particles are increased. Regression analysis of plaque size relative to the age of mice suggests that the initiation of atherosclerotic plaque development at the aortic root is slower in 129-apoE mice (intercept at 3.9 mo in females and 4.1 mo in males) than in B6-apoE mice (1.3 mo in females and 2.8 mo in males). In contrast, 129-apoE mice develop extensive plaques in the aortic arches earlier than B6-apoE mice. Distinct differences in the geometry of the aortic arch between the two strains suggest that anatomical differences may contribute to the effects of genetic background on atherosclerosis. The 129-apoE/B6-apoE pair thus provides a tool to study factors governing the relation between arterial geometry and the location of plaque development. Keywordsanimal model; atherosclerotic plaque distribution; cholesterol; aortic arch; aortic root; inbred mouse strain; ductus arteriosus Well-characterized animal models are essential for the study of common human diseases such as those involving the cardiovascular system. The first practical mouse model of atherosclerosis was developed by inactivating the gene coding for apolipoprotein E (apoE) (1-3). ApoE plays a central role in lipoprotein metabolism and is required for efficient receptor-mediated plasma clearance by the liver of chylomicron remnants and very low-density lipoprotein (VLDL)-remnant particles (4). Lack of apoE in the mutant mice results in an increased accumulation of cholesterol-enriched remnant particles and four times normal plasma cholesterol levels even Correspondence to: Dr. Nobuyo Maeda, Department of Pathology and Laboratory Medicine, The University of North Carolina at Chapel Hill, 701 Brinkhous-Bullitt Building, Chapel Hill, NC 27599-7525. Phone: 919-966-6912, Fax: 919-966-8800. E-mail: nobuyo@med.unc.edu.. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. when the mice are fed regular low-fat, low-cholesterol chow. The apoE-deficient mice spontaneously develop atherosclerotic plaques similar to those seen in humans (5,6), with the exception that the spontaneo...

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“…Doppler and 2D mModeguided echocardiography studies were performed on isofluraneanesthetized mice as described (15,16).…”

Section: Preparation Of Ianphdmentioning

confidence: 99%

Regulatable atrial natriuretic peptide gene therapy for hypertension

Schillinger

Tsai

Taffet

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Hypertension (HTN) is a disease that begins with dysfunctional renal-sodium excretion and progresses to a syndrome of highly elevated systolic, diastolic, and mean arterial pressures. Inadequacies in the therapy of HTN have led to the investigation of the gene therapy of this disease by using systemic overproduction of vasodilatory peptides, such as atrial natriuretic peptide (ANP). However, gene-therapy approaches to HTN using ANP are limited by the need for long-term ANP gene expression and, most important, control of ANP gene expression. Here, we introduce a helperdependent adenoviral vector carrying the mifepristone (Mfp)-inducible gene-regulatory system to control in vivo ANP expression. In the BPH͞2 mouse model of HTN, Mfp-inducible ANP expression was seen for a period of >120 days after administration of vector. Physiological effects of ANP, including decreased systolic blood pressure, increased urinary cGMP output, and decreases in heart weight as a percentage of body weight were also under the control of Mfp. Given these capabilities, this vector represents a paradigm for the gene therapy of HTN. adenovirus ͉ mifepristone-inducible H ypertension (HTN) is a disease that is characterized by chronically elevated arterial blood pressure that affects Ϸ25-35% of the population in developed countries, and it is one of the leading causes of morbidity and mortality in adults (1). Development of HTN is likely to involve defects in renal-sodium handling that are exacerbated by maladaptive activation of neurohormonal compensatory mechanisms. The morbidity and mortality caused by the hypertensive state are a consequence of detrimental effects that manifest predominantly in the heart, brain, and kidney and are referred to collectively as hypertensive end-organ disease. Typically, endorgan disease involves pathological left-ventricular hypertrophy, a propensity toward cerebrovascular accidents, and accelerated renal atherosclerosis (1, 2).The current therapy of HTN has been rationally designed to address the recognized causes of hypertensive pathophysiology, including impaired urinary-sodium excretion and neurohormonal compensatory-mechanism activation. Also, in recognition of the fact that hypertensive end-organ disease represents the true danger of chronically elevated arterial blood pressure, the main goals of antihypertensive therapy have evolved to include a reduction in blood pressure as well as prevention of cardiovascular, cerebrovascular, and renal pathology associated with elevated blood pressure (2, 3). However, a multitude of studies have revealed that no available drug therapy for HTN has the capability to cure the hypertensive state or reverse or prevent the pathological changes associated with hypertensive end-organ disease fully (2). As a result, therapeutic approaches to HTN involving gene therapy have been of recent interest.Atrial natriuretic peptide (ANP), a 27-aa peptide hormone with potent vasodilatory, natriuretic, diuretic, and antihypertrophic effects, is an attractive candidate gene product f...

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Hemodynamic changes in apolipoprotein E-knockout mice

Cited by 131 publications

References 31 publications

Effects of Isoflurane on Coronary Blood Flow Velocity in Young, Old and ApoE−/− Mice Measured by Doppler Ultrasound

Effects of Isoflurane on Coronary Blood Flow Velocity in Young, Old and ApoE−/− Mice Measured by Doppler Ultrasound

Anatomical differences and atherosclerosis in apolipoprotein E-deficient mice with 129/SvEv and C57BL/6 genetic backgrounds

Regulatable atrial natriuretic peptide gene therapy for hypertension

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