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Biomedical subjects

Erling Falk

Publications and source records attributed to Erling Falk.

30 records · Page 2Linked to original sources
PubMed2003

TDAG51 is induced by homocysteine, promotes detachment-mediated programmed cell death, and contributes to the cevelopment of atherosclerosis in hyperhomocysteinemia.

Hyperhomocysteinemia is an independent risk factor for cardiovascular disease and accelerates atherosclerosis in apoE-/- mice. Despite the observations that homocysteine causes endoplasmic reticulum (ER) stress and programmed cell death (PCD) in cultured human vascular endothelial cells, the cellular factors responsible for this effect and their relevance to atherogenesis have not been completely elucidated. We report here that homocysteine induces the expression of T-cell death-associated gene 51 (TDAG51), a member of the pleckstrin homology-related domain family, in cultured human vascular endothelial cells. This effect was observed for other ER stress-inducing agents, including dithiothreitol and tunicamycin. TDAG51 expression was attenuated in homozygous A/A mutant eukaryotic translation initiation factor 2 alpha mouse embryonic fibroblasts treated with homocysteine or tunicamycin, suggesting that ER stress-induced phosphorylation of eukaryotic translation initiation factor 2 alpha is required for TDAG51 transcriptional activation. Transient overexpression of TDAG51 elicited significant changes in cell morphology, decreased cell adhesion, and promoted detachment-mediated PCD. In support of these in vitro findings, TDAG51 expression was increased and correlated with PCD in the atherosclerotic lesions from apoE-/- mice fed hyperhomocysteinemic diets, compared with mice fed a control diet. Collectively, these findings provide evidence that TDAG51 is induced by homocysteine, promotes detachment-mediated PCD, and contributes to the development of atherosclerosis observed in hyperhomocysteinemia.

Animals↗
PubMed2003

Expansive remodeling is a response of the plaque-related vessel wall in aortic roots of apoE-deficient mice: an experiment of nature.

OBJECTIVE: In the present study, we (1) evaluated the apolipoprotein E-deficient (apoE(-/-)) mouse aortic root as a model for expansive remodeling in atherosclerosis and (2) examined whether remodeling at this site was due to dilation of the vessel wall beneath or flanking the plaque. METHODS AND RESULTS: Plaque area and length of the internal elastic lamina (IEL) were measured in aortic roots of apoE(-/-) mice at 11 weeks, 6 months, and 13 months of age. Expansive remodeling, indicated by IEL lengthening exceeding that of normal growth in wild-type C57BL/6 mice, was evident at 6 months of age and showed overcompensation (luminal enlargement) by 13 months of age. When the left coronary (LC), right coronary (RC), and noncoronary (NC) sinuses of the aortic root were looked at individually, remodeling was located to the LC at 6 months of age and to the LC and RC at 13 months of age. The remodeling response was closely related to local plaque area but unrelated to plaque formation in flanking sinuses. CONCLUSIONS: The aortic root of the apoE(-/-) mouse features a consistent remodeling response. In this model, expansive remodeling was a strictly local response of the plaque-related vessel wall.

Animals↗
PubMed2003

Hypercholesterolemia in pregnant mice does not affect atherosclerosis in adult offspring.

In humans, maternal hypercholesterolemia during pregnancy promotes microscopical fatty streaks in the children. The mechanism is unknown. Fatty streaks are clinically silent, and many of them regress and never develop into advanced atherosclerosis. The aim of this study was to investigate whether hypercholesterolemia in pregnant mice induced more advanced atherosclerosis in their adult progeny. Hypercholesterolemic (HC) apolipoprotein E knockout (apoE(-/-)) female mice were mated with normocholesterolemic (NC) wild-type (apoE(+/+)) males and vice versa. All parents were almost identical genetically except for apoE. Therefore, all progeny became genetically identical and heterozygous apoE(+/-). They were born of either HC (i.e. apoE(-/-)) or NC (i.e. apoE(+/+)) mothers. The progeny were killed 6 months after birth and the amount of atherosclerosis in the aortic root was assessed. Females developed more atherosclerosis than males (P<0.001) but, regardless of sex, maternal hypercholesterolemia during pregnancy had no influence on the amount of atherosclerosis in adult progeny. Males of HC mothers had lower plasma cholesterol levels than males of NC mothers. Thus, in mice, maternal hypercholesterolemia during pregnancy does not promote the development of advanced atherosclerosis in their adult progeny.

Animals↗
PubMed2003

Effects of vitamin supplementation and hyperhomocysteinemia on atherosclerosis in apoE-deficient mice.

It has been demonstrated that hyperhomocysteinemia (HHcy) accelerates atherosclerosis in apolipoprotein E-deficient (apoE(-/-)) mice. In this study, vitamin-defined chow diets were used to induce HHcy in apoE(-/-) mice in an attempt to identify possible pathogenic pathways. Six-week-old female apoE(-/-) mice were divided into seven groups: vitamin-defined purified chow diet alone (control), or same diet supplemented with either D,L-homocysteine (upward arrow Hcy) or L-homocystine (upward arrow Hcy-Hcy), or diet high in L-methionine (upward arrow Met), or diet high in B-vitamins (upward arrow vitamin), or diets deficient in folate (downward arrow folate) or vitamin B(6) ( downward arrow B(6)). Eighteen weeks later, plasma total homocysteine (tHcy), lipids and atherosclerotic plaque burden (aortic root, aortic arch, and brachiocephalic trunk) were measured. tHcy levels were similar in the upward arrow vitamin, downward arrow folate, downward arrow B(6) and control groups (9.2-10.1 micromol/l, NS), but elevated mildly in the upward arrow Hcy-Hcy group (16.1 micromol/l) and moderately in the upward arrow Met and upward arrow Hcy groups (53.6 and 51.5 micromol/l, respectively). Mice in the latter two groups had significantly more atherosclerosis in the aortic root. Although B vitamin-supplementation failed to lower tHcy levels, mice had less atherosclerosis in the aortic arch. In summary, dietary methionine and homocysteine, but not homocystine, enhanced the development of atherosclerosis. Supplementation with B vitamins appeared to confer homocysteine-independent protection against atherosclerosis. These results suggest that (1) there may be a threshold level below which homocysteine is not atherogenic; (2) the atherogenic effect of HHcy may be mediated via an intracellular pathway; and/or (3) the anti-atherogenic effect of B vitamins in normohomocysteinemic mice is independent of tHcy levels.

Animals↗
PubMed2003

Chronic renal failure accelerates atherogenesis in apolipoprotein E-deficient mice.

Cardiovascular mortality is 10 to 20 times increased in patients with chronic renal failure (CRF). Risk factors for atherosclerosis are abundant in patients with CRF. However, the pathogenesis of cardiovascular disease in CRF remains to be elucidated. The effect of CRF on the development of atherosclerosis in apolipoprotein E-deficient male mice was examined. Seven-week-old mice underwent 5/6 nephrectomy (CRF, n = 28), unilateral nephrectomy (UNX, n = 24), or no surgery (n = 23). Twenty-two weeks later, CRF mice showed increased aortic plaque area fraction (0.266 +/- 0.033 versus 0.045 +/- 0.006; P < 0.001), aortic cholesterol content (535 +/- 62 versus 100 +/- 9 nmol/cm(2) intimal surface area; P < 0.001), and aortic root plaque area (205,296 +/- 22,098 versus 143,662 +/- 13,302 micro m(2); P < 0.05) as compared with no-surgery mice; UNX mice showed intermediate values. The plaques from uremic mice contained CD11b-positive macrophages and showed strong staining for nitrotyrosine. Systolic BP and plasma homocysteine concentrations were similar in uremic and nonuremic mice. Plasma urea and cholesterol concentrations were elevated 2.6-fold (P < 0.001) and 1.5-fold (P < 0.001) in CRF compared with no-surgery mice. Both variables correlated with aortic plaque area fraction (r(2) = 0.5, P < 0.001 and r(2) = 0.3, P < 0.001, respectively) and with each other (r(2) = 0.5, P < 0.001). On multiple linear regression analysis, only plasma urea was a significant predictor of aortic plaque area fraction. In conclusion, the present findings suggest that uremia markedly accelerates atherogenesis in apolipoprotein E-deficient mice. This effect could not be fully explained by changes in BP, plasma homocysteine levels, or total plasma cholesterol concentrations. Thus, the CRF apolipoprotein E-deficient mouse is a new model for studying the pathogenesis of accelerated atherosclerosis in uremia.

Animals↗
PubMed2003

Thalidomide inhibits early atherogenesis in apoE-deficient mice.

Inflammation is present in all stages of atherosclerosis, from fatty streaks to rupture of mature plaques. Tumour necrosis factor (TNF)-alpha is expressed in atherosclerotic lesions but its role in atherogenesis has not been defined. To clarify the role of this cytokine, we administered thalidomide, a compound known to inhibit TNF-alpha production, to homozygous apolipoprotein E-deficient (apoE-/-) mice in order to examine the effect of thalidomide on the development of early atherosclerotic lesions. Twelve apoE-/- mice were randomized to receive either sustained-release thalidomide or placebo pellets implanted subcutaneously, and the amount of atherosclerosis was quantified six weeks later. Thalidomide was well tolerated and did not result in any changes in body weight. Mice treated with thalidomide had significantly smaller mean (7986 +/- 5189 vs 19607 +/- 10353 microns 2, p = 0.05) and maximum (15800 [12777-23675] vs 37169 [28000-41351] microns 2, p = 0.03) lesion sizes than those treated with placebo. Thus, thalidomide is capable of inhibiting the early development of atherosclerosis, presumably by inhibition of TNF-alpha secretion.

Animals↗
PubMed2002

[Children, fat and cardiovascular diseases].

Children do not normally develop atherosclerosis. However, they do develop fatty streaks in the aorta. These are reversible. During the first years of life dietary fat has an influence on blood lipids, and other traditional risk factors influence vascular function, but the consequences are unknown. As saturated fat has no positive effects, the Danish Nutrition Council recommends that the intake of saturated fat is reduced to 10 energy per cent from the age of 12 months. This can be accomplished with semi-skimmed milk (1.5% fat) instead of full-cream milk. During the first year of life, it is recommended that a teaspoon of fat is added to each serving of home made mashed food or porridge to prevent the diet from being so hypocaloric that it has a negative effect on growth.

Adult↗
PubMed2002

No effect of cyclooxygenase inhibition on plaque size in atherosclerosis-prone mice.

OBJECTIVE: To study the role of cyclooxygenase (COX) inhibition on the development of advanced atherosclerosis in apolipoprotein E-deficient (apoE(-/-)) mice. DESIGN: Sixty apoE(-/-) mice were divided into three groups: a control group, a group fed standard mouse chow supplemented with 0.0067% (wt/wt) MF Tricyclic (selective COX-2 inhibitor), and a group fed the diet supplemented with 0.0134% (wt/wt) sulindac (non-selective COX inhibitor). Four months later, the mice were killed and the atherosclerotic plaque area in the aortic root was measured. RESULTS: Mean body weights did not differ at any time. The MF Tricyclic and sulindac groups had drug plasma levels of 1.31 +/- 0.11 and 0.84 +/- 0.23 micro g/ml, respectively. Plasma total cholesterol and triglyceride values were similar in all three groups. A small difference in plasma levels of high-density lipoprotein cholesterol was found between the groups (p = 0.03). Advanced atherosclerotic plaques were present in mice from all three groups, but there was no difference in mean plaque size between the groups (p = 0.9). CONCLUSION: Neither selective COX-2 nor non-selective COX inhibition influenced the development of advanced atherosclerosis in apoE(-/-) mice.

Algorithms↗
PubMed2002

Remodelling of the left anterior descending artery in a porcine model of supravalvular aortic stenosis.

BACKGROUND: Knowledge of the adaptive mechanisms of structure and function of coronary arteries in response to physical stress is important in human health and disease. OBJECTIVE: To gain a better understanding of the adaptive mechanisms of morphology in the zero-stress state of the coronary arteries in a porcine model of hypertension and flow overload. METHODS: The effects of simultaneous increases in pressure and flow were examined by studying the left anterior decending (LAD) artery in supravalvular aortic stenosis (SVAS). In this model, the pressure is uniformly increased along the length of the LAD artery trunk, whereas the increase in flow is significantly greater in the proximal than in the distal artery. The longitudinal variation of vessel dimension, medial and adventitial area, opening angle and residual strains were examined in the LAD arteries of aortic-banded (n = 5) and control (n = 5) pigs. RESULTS: Our results show that the wall shear stress was normalized, whereas the circumferential stress was increased, in the proximal portion of the LAD artery after 5 weeks of SVAS. In the distal artery, both shear and circumferential stresses were normalized. The vessel wall area was also increased in the remodelled vessels as the result of an increase in the medial and adventitial area. CONCLUSION: The major conclusion of this study is that, in the SVAS model, the remodelling process of the coronary artery is consistent with normalization of shear stress despite an increase in the circumferential stress. Furthermore, the remodelling of the zero-stress state is also dominated by flow overload.

Adaptation, Physiological↗
PubMed2002

Macrophages are associated with lipid-rich carotid artery plaques, echolucency on B-mode imaging, and elevated plasma lipid levels.

OBJECTIVE: Atherosclerosis may be regarded as an inflammatory disease dominated by macrophages. We tested whether macrophages in carotid artery atherosclerotic plaques are associated with echolucency on B-mode ultrasound imaging, lipid levels, inflammatory markers, and aspirin use. METHODS: We studied 106 patients undergoing carotid endarterectomy having >/=50% carotid artery stenosis and previous ipsilateral hemispheric neurologic symptoms. RESULTS: Macrophages were particularly common in plaques with a high content of lipid and hemorrhage and, conversely, rare in plaques dominated by calcification and fibrous tissue. Macrophage density in carotid artery plaques classified by B-mode ultrasound imaging as echolucent (n = 56), intermediate (n = 25), or echorich (n = 25) was 1.8% +/- 0.2%, 1.5% +/- 0.4%, and 1.0% +/- 0.2% (+/-SE), respectively (analysis of variance, P =.02). A computer-generated measure of plaque echolucency, gray-scale median, was associated with increased macrophage density (r = -0.31; P =.002). Furthermore, plasma and low-density lipoprotein cholesterol levels were associated with carotid artery macrophage density (r = 0.26, P =.008 and r = 0.23, P =.02); this was most pronounced in patients with lipid-rich plaques. Macrophage density was not associated with plasma levels of acute-phase reactants. Finally, macrophage density in carotid artery plaques of users (n = 55) and nonusers of aspirin (n = 51) was 1.2% +/- 0.2% and 1.8% +/- 0.2% (t test, P =.01). CONCLUSIONS: Increased macrophage density in carotid atherosclerotic plaques was associated with lipid content, plaque echolucency, and increased plasma and low-density lipoprotein cholesterol levels. Furthermore, use of aspirin was associated with reduced macrophage density in carotid artery plaques.

Analysis of Variance↗
PubMedDate not supplied

The natural history of collagen and alpha-actin expression after coronary angioplasty.

BACKGROUND: Restenosis after percutaneous transluminal coronary angioplasty (PTCA) is a result of remodeling and deposition of new mass. The new mass is formed by invading and replicating cells and by extracellular matrix (ECM), of which collagens constitute the dominating component. Smooth muscle actin is an important element in cell contraction. We tested the hypothesis that the accumulation of collagen and actin correlates with the development of postinjury luminal narrowing. METHODS AND RESULTS: Thirty-five pigs underwent balloon angioplasty and were killed 0, 1, 4, 7, 14, 28, and 56 days later. Tissue samples from the left circumflex artery were in paraffin, sectioned, and immunostained for Collagen Types I and III and alpha1-smooth muscle actin. Collagen accumulation was measured separately in intima, media, and adventitia using computerized semiautomatic planimetry. The injury produced a strong healing response, with a marked accumulation of collagen in all three vessel wall layers. However, the accumulation in adventitia began surprisingly early (1 to 4 days after PTCA) and stopped at Day 7, i.e., before luminal narrowing occurred (14 to 28 days after PTCA in our model). Furthermore, a conspicuous accretion of collagen occurred in the injured area of the medial layer. This response attenuated 14 days after PTCA. Neointimal collagen accumulation took place parallel to neointima formation 2 to 4 weeks after injury. Extramedial smooth muscle actin occurred predominantly from Days 4 to 14 in neointima. Only small quantities of actin were observed in the (neo-)adventitia. Furthermore, adventitial actin was a temporary phenomenon that disappeared between Days 14 and 28. CONCLUSION: Adventitial and medial collagen deposition apparently occurs before luminal narrowing, indicating that the bulk of new mass in adventitia and media is not the cause of vessel remodeling, but possibly stabilizes the vessel wall and impairs compensatory outward remodeling. The accumulation of actin-positive cells and collagen takes place in neointima parallel to luminal narrowing, which suggests that a contraction within the neointimal mass may contribute to the remodeling process.

Actins↗