| 1. |
- Andersson, Irene, 1978, et al.
(författare)
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Endothelial dysfunction in growth hormone transgenic mice
- 2006
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Ingår i: Clinical Science. - 0143-5221 .- 1470-8736. ; 110:2, s. 217-25
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Tidskriftsartikel (refereegranskat)abstract
- Acromegaly [overproduction of GH (growth hormone)] is associated with cardiovascular disease. Transgenic mice overexpressing bGH (bovine GH) develop hypertension and hypercholesterolaemia and could be a model for cardiovascular disease in acromegaly. The aims of the present study were to investigate the effects of excess GH on vascular function and to test whether oxidative stress affects endothelial function in bGH transgenic mice. We studied the ACh (acetylcholine)-induced relaxation response in aortic and carotid rings of young (9-11 weeks) and aged (22-24 weeks) female bGH transgenic mice and littermate control mice, without and with the addition of a free radical scavenger {MnTBAP [Mn(III)tetrakis(4-benzoic acid)porphyrin chloride]}. We also measured mRNA levels of eNOS (endothelial nitric oxide synthase) and EC-SOD (extracellular superoxide dismutase). Intracellular superoxide anion production in the vascular wall was estimated using a dihydroethidium probe. Carotid arteries from bGH transgenic mice had an impaired ACh-induced relaxation response (young, 46 +/- 7% compared with 69 +/- 8%; aged, 52 +/- 5% compared with 80 +/- 3%; P < 0.05), whereas endothelial function in aorta was intact in young but impaired in aged bGH transgenic mice. Endothelial dysfunction was corrected by addition of MnTBAP in carotid arteries from young mice and in aortas from aged mice; however, MnTBAP did not correct endothelial dysfunction in carotid arteries from aged bGH transgenic mice. There was no difference in intracellular superoxide anion production between bGH transgenic mice and control mice, whereas mRNA expression of EC-SOD and eNOS was increased in aortas from young bGH transgenic mice compared with control mice (P < 0.05). We interpret these data to suggest that bGH overexpression is associated with a time- and vessel-specific deterioration in endothelial function, initially caused by increased oxidative stress and later by other alterations in vascular function.
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| 2. |
- Andersson, Irene, 1978, et al.
(författare)
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Increased atherosclerotic lesion area in apoE deficient mice overexpressing bovine growth hormone
- 2006
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Ingår i: Atherosclerosis. - : Elsevier BV. - 0021-9150. ; 188:2, s. 331-40
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Tidskriftsartikel (refereegranskat)abstract
- Human growth hormone (GH) excess is linked to increased cardiovascular morbidity and mortality. However, little is known about the effect of GH excess on atherosclerosis. We developed a new mouse model to assess the hypothesis that GH overexpression accelerates atherosclerotic lesion formation. apoE(-/-) mice were crossed with bovine GH (bGH) transgenic mice to yield apoE(-/-) mice overexpressing bGH (apoE(-/-)/bGH). The mice were fed either standard or Western diet. At 22 weeks, atherosclerotic lesion area of thoracic aorta was larger in apoE(-/-)/bGH mice compared with littermate apoE(-/-) mice fed either diet (standard: +161+/-50%, Western: +430+/-134%). Aortic sinus lesions were more severe in apoE(-/-)/bGH mice fed standard diet compared with littermate apoE(-/-) mice. apoE(-/-)/bGH mice had lower (VLDL+LDL)/HDL ratios compared with littermate apoE(-/-) mice, while systolic blood pressure was higher in apoE(-/-)/bGH mice, irrespective of diet. The levels of serum amyloid A and hepatic CRP mRNA were higher in apoE(-/-)/bGH mice than in littermate apoE(-/-) mice. In conclusion, this study shows that excess GH augments the development of atherosclerosis in apoE(-/-) mice. The mechanisms could be direct effects of GH on cellular processes in the vessel wall or the result of concomitant processes such as hypertension or a general inflammatory state.
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| 3. |
- Bernberg, Evelina, 1981, et al.
(författare)
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Effects of social isolation and environmental enrichment on atherosclerosis in ApoE-/- mice
- 2008
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Ingår i: Stress. - 1607-8888 .- 1025-3890. ; 11:5, s. 381-9
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Tidskriftsartikel (refereegranskat)abstract
- Social support and a stimulating environment have been suggested to reduce stress reactions and cardiovascular risk. The aim of this study was to assess the role of environmental enrichment and social interaction for development of atherosclerosis in atherosclerosis prone mice. Male ApoE-/- mice were divided into four groups and followed during 20 weeks: (i) enriched environment (E, n=12), (ii) deprived environment (ED, n=12), (iii) enriched environment with exercise (E-Ex, n=12) and (iv) socially deprived by individual housing (SD, n=10). Plasma lipid and cytokine concentrations were measured. Atherosclerosis was quantified in cross-sections of innominate artery and en face in thoracic aorta. Plaque area was significantly increased in SD mice in the innominate artery (P<0.05 vs. all other groups), but not in the thoracic aorta. Plasma lipids were increased in SD mice (P<0.001 vs. all for total cholesterol, P<0.05 vs. E and P<0.01 vs. ED for triglycerides). Plasma concentration of granulocyte-colony stimulating factor (G-CSF) was decreased in SD mice compared to E mice (P<0.05). Thus, social isolation increased atherosclerosis and plasma lipids in ApoE-/- mice. Reduction in plasma G-CSF levels may hamper endothelial regeneration in the atherosclerotic process. While environmental enrichment did not affect atherosclerosis, social isolation accelerated atherosclerosis.
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| 4. |
- Gan, Li-Ming, 1969, et al.
(författare)
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Non-invasive imaging of coronary arteries in living mice using high-resolution echocardiography
- 2004
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Ingår i: Scand Cardiovasc J. - : Informa UK Limited. - 1401-7431. ; 38:2, s. 121-6
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: In vivo mouse coronary artery circulation is still largely unknown. We demonstrate here in vivo coronary flow velocity profiles in anesthesized mice using a novel high-resolution ultrasound technique. METHODS: Seven 10-week-old C57/Bl6 mice were used for ultrasonographic examination under anesthesia. An Acuson Sequoia 512 echocardiograph with a Microson 15L8 transducer was used. Left coronary artery (LCA) anatomy was mapped in situ. RESULTS: The proximal, mid LCA and its anterior (A-LCA) and lateral (L-LCA) branches could be visualized and coronary flow velocity was reproducibly recorded in all animals. Peak flow velocity was 31.3 +/- 1.5 and 20.7 +/- 2.3 cm/s in the mid LCA and L-LCA branches, respectively. Mean flow velocity was 18.4 +/- 0.7 and 13.8 +/- 1.5 cm/s in the respective vessels. Both the peak and mean flow velocities were higher in the mid LCA than in the distal part of the L-LCA (p = 0.006 and 0.01, respectively). Measurements of the velocity time integral show percentage systolic flow was 15.7 +/- 1.6% and 10.2 +/- 1.4% in the mid LCA and L-LCA, respectively. CONCLUSION: Despite the extremely high heart rate in mice, there are striking similarities between murine and human coronary flow velocity profiles. The presented technique and findings confirm the relevance of the mouse as an animal model in cardiovascular research.
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| 5. |
- Hägg Samuelsson, Ulrika, 1973, et al.
(författare)
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Gene expression profile and aortic vessel distensibility in voluntarily exercised spontaneously hypertensive rats: potential role of heat shock proteins
- 2005
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Ingår i: Physiol Genomics. - 1531-2267 .- 1094-8341. ; 22:3, s. 319-26
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Tidskriftsartikel (refereegranskat)abstract
- Physical exercise is considered to be beneficial for cardiovascular health. Nevertheless, the underlying specific molecular mechanisms still remain unexplored. In this study, we aimed to investigate the effects of voluntary exercise on vascular mechanical properties and gene regulation patterns in spontaneously hypertensive rats. By using ultrasound biomicroscopy in an ex vivo perfusion chamber, we studied the distensibility of the thoracic aorta. Furthermore, exercise-induced gene regulation was studied in aortae, using microarray analysis and validated with real-time PCR. We found that distensibility was significantly improved in aortas from exercising compared with control rats (P < 0.0001). Exercising rats demonstrated a striking pattern of coordinated downregulation of genes belonging to the heat shock protein family. In conclusion, voluntary exercise leads to improved vessel wall distensibility and reduced gene expression of heat shock protein 60 and 70, which may indicate decreased oxidative stress in the aortic vascular wall.
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| 6. |
- Hägg Samuelsson, Ulrika, 1973, et al.
(författare)
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Physical exercise capacity is associated with coronary and peripheral vascular function in healthy young adults.
- 2005
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Ingår i: American journal of physiology. Heart and circulatory physiology. - : American Physiological Society. - 0363-6135 .- 1522-1539. ; 289:4
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Tidskriftsartikel (refereegranskat)abstract
- Short-term exercise training has been shown to improve cardiovascular function, whereas long-term effects of a physically active lifestyle, on coronary artery function in particular, are still not well studied. We explored possible relationships between physical exercise capacity and coronary and peripheral vascular function in healthy young adults. Twenty-nine healthy young male and female volunteers participated in the study. They underwent 1) basic clinical and echocardiographic characterization, 2) coronary flow velocity reserve (CFVR) measurement of the left anterior descending coronary artery (LAD), 3) common carotid artery (CCA) intima-media thickness (IMT) measurement, 4) assessment of CCA stiffness index (SI), 5) forearm flow-mediated vasodilation (FMD), and 6) submaximal exercise test. The calculated weight-adjusted maximal oxygen uptake capacity (Vo(2 max)(c)) was positively correlated to LAD CFVR and inversely correlated to IMT and SI. Also, subjects with high compared with moderate exercise capacity had higher FMD. In addition, subjects with LAD CFVR in the upper median had greater ratios between endothelium-dependent and -independent vasodilation in the forearm and lower SI in CCA. High exercise capacity due to a physically active lifestyle is associated with high coronary and peripheral artery function, indicating an early protective role of physical exercise for cardiovascular health.
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| 7. |
- Hägg Samuelsson, Ulrika, 1973, et al.
(författare)
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Voluntary physical exercise and coronary flow velocity reserve: a transthoracic colour Doppler echocardiography study in spontaneously hypertensive rats
- 2005
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Ingår i: Clin Sci (Lond). - 0143-5221. ; 109:3, s. 325-34
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Tidskriftsartikel (refereegranskat)abstract
- In the present study, we have developed and demonstrated a coronary artery imaging protocol in rats using transthoracic high-frequency CDE (colour Doppler echocardiography) to investigate the potential direct effects of exercise on CFVR (coronary flow velocity reserve). SHR (spontaneously hypertensive rats) performed voluntary exercise for 6 weeks. Rats were then submitted to ultrasonographic examination and CFVR measurements. The LAD (left anterior descending coronary artery) was visualized using transthoracic CDE in a modified parasternal long-axis view. Doppler measurement was made in mid-LAD during baseline and adenosine-induced hyperaemic condition. Gene and protein expression in cardiac tissue were studied using real-time PCR and immunohistochemistry. Adenosine infusion significantly (P<0.001, as determined by ANOVA) decreased HR, without affecting blood pressure in anaesthetized SHR. A significantly greater adenosine dose-dependent response was seen in exercised rats compared with controls (P=0.02, as determined by ANOVA). The baseline flow velocity in mid-LAD was 0.33+/-0.06 and 0.41+/-0.14 m/s in the exercised and control animals respectively (P value was not significant). The maximum adenosine-induced response was reached at a dose of 140 microg.kg-1 of body weight.min-1, and CFVR averaged at 2.6+/-0.53 and 1.5+/-0.24 in exercised and control animals respectively (P<0.01). Gene expression of CuZnSOD was up-regulated by 21% in exercised animals compared with controls (1.1+/-0.16 compared with 0.89+/-0.09; P<0.01), whereas eNOS expression was unchanged. In conclusion, CFVR in rats can be non-invasively assessed using CDE with high feasibility. Physical exercise is associated with improved CFVR and antioxidative capacity in SHR.
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| 8. |
- Hägg Samuelsson, Ulrika, 1973, et al.
(författare)
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Voluntary physical exercise-induced vascular effects in spontaneously hypertensive rats
- 2004
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Ingår i: Clin Sci (Lond). - 0143-5221. ; 107:6, s. 571-81
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Tidskriftsartikel (refereegranskat)abstract
- Forced training has been shown to have beneficial vascular effects in various animal exercise models. In the present study, we explored possible physiological and molecular effects of voluntary physical exercise on various vascular beds. SHR (spontaneously hypertensive rats) performed voluntary exercise for 5 weeks in a computerized wheel cage facility. Ex vivo myograph studies revealed an increased sensitivity of the ACh (acetylcholine)-mediated vasodilation in resistance arteries of the exercised animals (ED50=15.0+/-3.5 nmol/l) compared with the controls (ED50=37.0+/-8.8 nmol/l; P=0.05). The exercise/control difference was abolished after scavenging reactive oxygen radicals. In conduit arteries, ACh induced a similar vasodilatory response in both groups. The in vivo aortic wall stiffness, assessed by means of Doppler tissue echography, was significantly lower in the exercising animals than in controls. This was demonstrated by significantly increased peak systolic aortic wall velocity (P=0.03) and the velocity time integral (P=0.01) in exercising animals compared with controls. The relative gene expression of eNOS (endothelial nitric oxide synthase) was similar in both groups of animals, whereas Cu/ZnSOD (copper/zinc superoxide dismutase) gene expression was significantly increased (+111%; P=0.0007) in the exercising animal compared with controls. In conclusion, voluntary physical exercise differentially improves vascular function in various vascular beds. Increased vascular compliance and antioxidative capacity may contribute to the atheroprotective effects associated with physical exercise in conduit vessels.
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| 9. |
- Johansson, Maria, 1977, et al.
(författare)
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Angiotensin II, type 2 receptor is not involved in the angiotensin II-mediated pro-atherogenic process in ApoE-/- mice
- 2005
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Ingår i: J Hypertens. - 0263-6352. ; 23:8, s. 1541-9
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Angiotensin II (Ang II) accelerates atherogenesis in ApoE mice via the angiotensin II, type 1 receptor (AT1) while the type 2 receptor (AT2) is suggested to counteract atherogenesis. To confirm and further explore this possibility, we studied the effect of AT2 receptor antagonism on Ang II-accelerated atherosclerosis. METHODS: ApoE mice were fed a standard or high cholesterol diet (1.25%) for 4 weeks. Mice on each diet were treated with either Ang II (0.5 microg/kg per min) or Ang II in combination with PD123319 (3 mg/kg per day). Plaque distribution was assessed by en face quantification of the thoracic aorta and in cross-sections of the aortic root. Mean arterial pressure (MAP) was measured. AT1 and AT2 receptor expression were analysed using real-time polymerase chain reaction (PCR) and the localization of the AT2 receptor protein confirmed with immunohistochemistry. RESULTS: Ang II infusion increased MAP only in mice on a standard diet (P < 0.001). Regardless of diet, Ang II-infused mice had 22-30 times increased plaque area in the thoracic aorta (P < 0.001 for both). Ang II had no effect on plaque in the aortic root. Plaque area was not affected by PD123319. AT2 receptor was heavily expressed in the plaques and increased six- to ninefold by a high cholesterol diet and Ang II infusion (P < 0.01). CONCLUSION: Ang II increases the extent of atherosclerosis in ApoE mice. Despite up-regulation of the AT2 receptor, we found no support for an effect of the AT2 receptor on atherogenesis in this model.
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| 10. |
- Johansson, Maria E, 1977, et al.
(författare)
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Blood pressure is the major driving force for plaque formation in aortic-constricted ApoE-/- mice
- 2006
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Ingår i: Journal of Hypertension. - : Ovid Technologies (Wolters Kluwer Health). - 0263-6352. ; 24:10, s. 2001-8
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Using an aortic constriction model in mice, we studied whether the increase in pressure or the activation of the renin-angiotensin system (RAS) and its main receptors is the main driving force for plaque progression. METHODS: Male ApoE mice underwent sham surgery or placement of a suprarenal silver clip around the aorta (AoC). Half the group was treated with the selective AT1 receptor antagonist losartan (30 mg/kg per day) for 4 weeks. RESULTS: Anesthetized mean arterial pressure (MAP) was increased in AoC mice compared to sham (106 +/- 3 versus 90 +/- 1 mmHg, P < 0.001). Losartan reduced MAP in sham mice (78 +/- 2 mmHg, P < 0.01) but not in AoC (AoC losartan 104 +/- 2 mmHg). Plasma renin concentration (PRC) was increased in AoC mice compared to sham [1.6 +/- 0.3 versus 0.8 +/- 0.2 milliGoldblatt units (mGU)/ml, P < 0.001]. Losartan treatment augmented this difference (18.7 +/- 3.7 versus 4.6 +/- 1.7 mGU/ml, P < 0.01). AT2 receptor mRNA expression was increased 5.8-fold by aortic constriction in thoracic aorta (P < 0.05) and the major site for expression of the AT2 receptor protein was within the plaques. The plaque area was increased in AoC mice compared to sham (0.61 +/- 0.09 versus 0.07 +/- 0.01%, P < 0.001); however, losartan did not alter plaque area. CONCLUSIONS: Our data do not support a role for the AT1 receptor in the progression of atherosclerosis in this model, since blockade with losartan did not alter plaque distribution. Furthermore, we found no support for the counteraction of atherogenesis by increased activity of the RAS acting on the AT2 receptor. Our data suggest that increased pressure is the main driving force for atherosclerosis in this model.
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