Acta Physiologica Scandinavica

2005

DOI: 10.1111/j.1365-201x.2005.01421.x

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Electrocardiographic characterization of stress‐induced myocardial infarction in atherosclerotic mice

Anne-Louise Hemdahl

¹

,

Giuseppina Caligiuri

²

,

Göran K. Hansson

³

et al.

Abstract: This is the first mouse model showing that increased STU-area variability is indicative of MI development in atherosclerotic mice following ischaemic stress. Furthermore, our findings suggest a two-phase pathway for the infarction development: an initial phase comprising a transient ischaemic response which triggers a delayed second phase of ischaemia and MI.

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Small-animal Models Of Plaque Destabilisation and Disruption1

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Cited by 10 publications

(8 citation statements)

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“…Epidemiologic evidence supports the idea that stress, which can activate the sympathetic nervous system, is a risk factor for acute cardiovascular events (10,40). Hemdahl et al (17) reported that both stress and hypoxic stimulation could trigger myocardial infarction in apoE Ϫ/Ϫ /LDLR Ϫ/Ϫ mice. In the present study, stress acted as an ideal physiological trigger instead of pharmacological triggers to induce plaque disruption.…”

Section: Discussionmentioning

confidence: 92%

Atherosclerotic plaque disruption induced by stress and lipopolysaccharide in apolipoprotein E knockout mice

N¹,

Wang²,

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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To establish an animal model with disruptions of atherosclerotic plaques, 96 male apolipoprotein E knockout (apoE(-/-)) mice were randomly divided into stress, lipopolysaccharide (LPS), stress+LPS, and control groups (n = 24 each). All mice were fed a high-fat diet throughout the experiment, and carotid atherosclerotic lesions were induced by placement of a constrictive perivascular collar. Four weeks after surgery, mice in the LPS and stress+LPS groups were intraperitoneally injected with LPS (1 mg/kg twice per week for 8 wk). Eight weeks after surgery, mice in the stress and stress+LPS groups were treated with intermittent physical stress (electric foot shock and noise stimulation) for 4 wk. Morphological analysis revealed a plaque disruption rate of 16.7% in control, 34.8% in LPS, 54.2% in stress, and 60.9% in stress+LPS groups. The disruption rates in stress and stress+LPS groups were both significantly higher than those of controls (P = 0.007 and P = 0.002, respectively). Luminal thrombosis secondary to plaque disruption was observed only in the stress+LPS group. Both stress and LPS stimulation significantly decreased fibrous cap thickness and increased macrophage and lipid contents in plaques. Moreover, the combination of stress and LPS stimulation further lowered cap thickness and enhanced accumulation of macrophages and expression of inflammatory cytokines and matrix metalloproteinases. Stress activated the sympathetic nervous system, as manifested by increased blood pressure and flow velocity. Plasma fibrinogen levels were remarkably elevated in the stress and stress+LPS groups. In conclusion, stress- and LPS-costimulated apoE(-/-) mice provide a useful model for studies of plaque vulnerability and interventions.

“…Epidemiologic evidence supports the idea that stress, which can activate the sympathetic nervous system, is a risk factor for acute cardiovascular events (10,40). Hemdahl et al (17) reported that both stress and hypoxic stimulation could trigger myocardial infarction in apoE Ϫ/Ϫ /LDLR Ϫ/Ϫ mice. In the present study, stress acted as an ideal physiological trigger instead of pharmacological triggers to induce plaque disruption.…”

Section: Discussionmentioning

confidence: 92%

Atherosclerotic plaque disruption induced by stress and lipopolysaccharide in apolipoprotein E knockout mice

N¹,

Wang²,

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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To establish an animal model with disruptions of atherosclerotic plaques, 96 male apolipoprotein E knockout (apoE(-/-)) mice were randomly divided into stress, lipopolysaccharide (LPS), stress+LPS, and control groups (n = 24 each). All mice were fed a high-fat diet throughout the experiment, and carotid atherosclerotic lesions were induced by placement of a constrictive perivascular collar. Four weeks after surgery, mice in the LPS and stress+LPS groups were intraperitoneally injected with LPS (1 mg/kg twice per week for 8 wk). Eight weeks after surgery, mice in the stress and stress+LPS groups were treated with intermittent physical stress (electric foot shock and noise stimulation) for 4 wk. Morphological analysis revealed a plaque disruption rate of 16.7% in control, 34.8% in LPS, 54.2% in stress, and 60.9% in stress+LPS groups. The disruption rates in stress and stress+LPS groups were both significantly higher than those of controls (P = 0.007 and P = 0.002, respectively). Luminal thrombosis secondary to plaque disruption was observed only in the stress+LPS group. Both stress and LPS stimulation significantly decreased fibrous cap thickness and increased macrophage and lipid contents in plaques. Moreover, the combination of stress and LPS stimulation further lowered cap thickness and enhanced accumulation of macrophages and expression of inflammatory cytokines and matrix metalloproteinases. Stress activated the sympathetic nervous system, as manifested by increased blood pressure and flow velocity. Plasma fibrinogen levels were remarkably elevated in the stress and stress+LPS groups. In conclusion, stress- and LPS-costimulated apoE(-/-) mice provide a useful model for studies of plaque vulnerability and interventions.

“…The goal of the current study was to characterize the influence of sex and age on heart protein expression. Due to the scarcity of human tissue samples, we first employed C57BL/6 mice, a standard mouse strain that has been proven to be a pertinent model for studying human heart diseases (17,18). The use of well-characterized inbred mouse strains reduces the possible influences of genetic polymorphisms on protein expression patterns, a problem involved in investigations of human individuals.…”

Section: Discussionmentioning

confidence: 99%

Heart protein expression related to age and sex in mice and humans

¹

,

Mao³

et al. 2007

Int J Mol Med

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Cardiovascular diseases are known to manifest different clinical symptoms in men and women. Basically this is due to gender-specific genotypes and sexual hormones. We studied gender specificity on the protein expression level in the mouse and human heart, with particular emphasis on the age-dependency of sex-specific protein expression. We first studied the heart proteome in female and male mice at 14 and 100 weeks of age using two-dimensional electrophoresis and mass spectrometry. Protein pattern comparison in young and old mice revealed 7 and 22 protein spots with sex-related expression profiles, respectively. Four proteins co-changed in both age groups. The variant protein spots were identified and revealed 10 distinct proteins and several isoforms thereof: α1-antitrypsin (3 isoforms), apolipoprotein A2 (2 isoforms), apolipoprotein A4 (3 isoforms), apolipoprotein E, apolipoprotein J (3 isoforms), carbonic anhydrase 2 (6 isoforms), desmin, nitrilase 1, peroxiredoxin 2 and Rho GDP dissociation inhibitor α (2 isoforms). More sex-related proteins were detected in old than in young mice. Through 2DE protein pattern and immunoblot comparisons, six of the variant proteins detected in mice were also observed to change in an age-and sex-dependent manner in the human heart. The age and/or gender-related proteins and species differences in this regard are discussed in terms of cardiovascular disease.

“…Male ApoE (Ϫ͞Ϫ) mice and ApoE (Ϫ͞Ϫ) ϫ LDLR (Ϫ͞Ϫ) mice on the C57BL͞6J background were obtained from Malling Beck (Ry, Denmark) after they were weaned. The ApoE (Ϫ͞Ϫ) ϫ LDLR (Ϫ͞Ϫ) mice were fed a Western-type diet containing cornstarch, glucose, sucrose, cocoa butter, cellulose, minerals, vitamin mix, 0.15% cholesterol, and 21% total fat (wt͞wt) for 8 months (24). The ApoE (Ϫ͞Ϫ) mice were fed standard chow for 25 weeks.…”

Section: Methodsmentioning

confidence: 99%

Expression of 5-lipoxygenase and leukotriene A ₄ hydrolase in human atherosclerotic lesions correlates with symptoms of plaque instability

¹

,

²

,

³

et al. 2006

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

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Atherosclerosis is an inflammatory disorder involving complex interactions between vascular wall cells and invading inflammatory cells (14). Genetically modified mouse models of atherosclerosis, based on two pivotal genes of lipid metabolism, i.e., apolipoprotein E (ApoE) and the low-density lipoprotein receptor (LDLR), have been crossed with mice deficient in a specific gene of the LT cascade, e.g., 5-LO and BLT 1 , to investigate the impact of the gene product on the atherosclerotic process (9,(15)(16)(17).In the present study we examined the expression of 5-LO, FLAP, LTA4H, LTC4S, and the receptors BLT 1 , BLT 2 , CysLT 1 , and CysLT 2 in human carotid plaques and aortic lesions from both ApoE (Ϫ͞Ϫ) and compound ApoE (Ϫ͞Ϫ) ϫ LDLR (Ϫ͞Ϫ) mice. In contrast to the mouse models, we find that both 5-LO and LTA4H are expressed at increased levels and colocalize within human atherosclerotic lesions, with expression levels correlating with recent or ongoing symptoms of plaque instability. We also report that a selective inhibitor of LTA4H can block LTB 4 biosynthesis in plaque tissue, thus identifying LTA4H as a potential target for development of drugs for prevention and treatment of atherosclerosis and acute atherothrombotic events. Results Expression of 5LO, FLAP, LTA4H, and LTC4S mRNA in Human CarotidPlaque and Mouse Atherosclerotic Aorta. In the human carotid atherosclerotic lesions, the transcript levels of 5-LO, FLAP, and LTA4H were high, corresponding to a 7.5-fold (7.5 Ϯ 4.1, P Ͻ 0.001), 2.7-fold (2.7 Ϯ 1.3, P ϭ 0.003), and nearly 2-fold (1.9 Ϯ 1.0, P ϭ 0.03) increase relative to normal iliac arteries, respectively (Fig. 1A). In contrast, the levels of LTC4S mRNA were not significantly different from controls.In the ApoE (Ϫ͞Ϫ) mouse aorta, 5-LO and LTA4H mRNA levels were essentially unaltered, whereas FLAP and LTC4S mRNA showed a tendency to increase relative tissue from wild-type C57BL͞6J mice (Fig. 1B). In ApoE (Ϫ͞Ϫ) ϫ LDLR (Ϫ͞Ϫ) mice, the expression pattern of the enzymes was essentially the same as in ApoE (Ϫ͞Ϫ) mice, except that LTA4H mRNA levels were significantly increased (1.7 Ϯ 0.3, P ϭ 0.01) (Fig. 1C). Expression of 5-LO, FLAP, and LTA4H Protein in Human and MouseAtherosclerotic Lesions. Staining of human carotid plaque demonstrated prominent expression of 5-LO, FLAP, and LTA4H in intimal lesion areas that also stained positively for human macrophage marker CD163 (Fig. 2). The distribution of 5-LO,

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