| 1. |
- Bollano, Entela, 1970, et al.
(author)
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Cardiac remodeling rather than disturbed myocardial energy metabolism is associated with cardiac dysfunction in diabetic rats.
- 2006
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In: Int J Cardiol. - : Elsevier BV. - 0167-5273.
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Journal article (peer-reviewed)abstract
- BACKGROUND: Diabetes mellitus (DM) alters the energy substrate metabolism in the heart and the early sign of diabetic cardiomyopathy is the diastolic dysfunction. Although it is known that the extracellular matrix must be altered in the presence of diabetes, its local regulation has not been fully elucidated. Our aim was to evaluate in vivo left ventricular (LV) structure; function and bioenergetics in streptozotocin (STZ) induced diabetes mellitus. METHODS: Cardiac function was evaluated using echocardiography in anesthetized Sprague-Dawley rats 12 weeks after injection of STZ and in age-matched control rats before and after atrial pacing. In vivo (31)P magnetic resonance spectroscopy was done to measure the phosphocreatine (PCr) to ATP ratio. Myocardial protein expression of metalloproteinases MMP-2, -9, tissue inhibitor TIMP-1, -2 and collagen was measured using Western blot. RESULTS: Bodyweight (BW) was decreased in diabetic rats. Heart weight/BW and LV mass/BW ratios were higher in diabetic animals compared to controls (2.3+/-08 vs 2.1+/-08 mg/g p<0.05). Heart rate was lower in diabetic rats (293+/-20 vs 394+/-36 bpm p<0.05). The velocity of circumferential shortening and peak aortic velocity were lower in diabetic animals and were more pronounced during atrial pacing. The basal PCr/ATP ratio was not different in the two groups. Total collagen was higher in diabetic rats (3.8+/-0.3 vs 2.9+/-01 mg/g, p<0.05). Protein expression of MMP-2 was significantly diminished in diabetic rats by approximately 60%, while MMP-9, TIMP-1 and -2 were unchanged. CONCLUSION: Streptozotocin induced diabetes led to increased LV/bodyweight, increased collagen content, and diminished MMP-2 with no change in PCr/ATP. Therefore, remodeling rather than disturbed energetics may underlie diabetic cardiomyopathy.
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| 2. |
- Buvall, Lisa, 1976, et al.
(author)
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Phenotype of early cardiomyopathic changes induced by active immunization of rats with a synthetic peptide corresponding to the second extracellular loop of the human beta-adrenergic receptor
- 2006
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In: Clin Exp Immunol. - : Oxford University Press (OUP). - 0009-9104. ; 143:2, s. 209-15
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Journal article (peer-reviewed)abstract
- In the failing human heart, due to idiopathic dilated cardiomyopathy, it has been suggested that the beta1-adrenergic receptor (beta1AR) is a potential pathogenic autoantigen. The aim of the present study was to investigate whether immunization of rats with a synthetic peptide corresponding to the second extracellular loop of the beta1AR (beta1AR EC(II)) was able to induce the early stage of cardiomyopathy and also to investigate immunological and receptor functional parameters at a transcriptional level to permit insights into the autoimmune mechanism in cardiomyopathy. Eleven Whistar Fur rats were immunized with a beta1AR EC(II) peptide (H26R) once a month during 12 months and seven control rats were injected with vehicle according to the same procedure used for the immunized group. Cardiac function, beta1AR autoantibodies and their functional effects on cardiomyocytes were analysed. beta1AR receptor signalling, immunological and cardiomyocyte stretch markers were determined on transcriptional level. In H26R immunized rats, beta1AR autoantibodies were shown to be present and functionally active, cardiac functions in terms of fractional shortening were decreased and beta1-adrenergic receptor kinase (GRK2) mRNA were increased compared with the control group. These data have shown that immunization of rats with a putative antigenic peptide was able to induce an early stage phenotype of cardiomyopathy in the form of cardiac dysfunction and up-regulation of GRK2 as the first step in the desensitization process of the beta1AR, implying the pathological importance of the beta1AR autoantibody.
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| 3. |
- Egecioglu, Emil, 1977, et al.
(author)
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Growth hormone receptor deficiency in mice results in reduced systolic blood pressure and plasma renin, increased aortic eNOS expression, and altered cardiovascular structure and function
- 2007
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In: AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 292:5
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Journal article (peer-reviewed)abstract
- To study the role of the growth hormone receptor (GHR) in the development of cardiovascular structure and function, female GHR gene-disrupted or knockout (KO) and wild-type (WT) mice at age 18 wk were used. GHR KO mice had lower plasma renin levels (12 ± 2 vs. 20 ± 4 mGU/ml, P < 0.05) and increased aortic endothelial NO synthase (eNOS) expression (146%, P < 0.05) accompanied by a 25% reduction in systolic blood pressure (BP, 110 ± 4 vs. 147 ± 3 mmHg, P < 0.001) compared with WT mice. Aldosterone levels were unchanged, whereas the plasma potassium concentration was elevated by 14% ( P < 0.05) in GHR KO. Relative left ventricular weight was 14% lower in GHR KO mice ( P < 0.05), and cardiac dimensions as analyzed by echocardiography were similarly reduced. Myograph studies revealed a reduced maximum contractile response in the aorta to norepinephrine (NE) and K+ ( P < 0.05), and aorta media thickness was decreased in GHR KO ( P < 0.05). However, contractile force was normal in mesenteric arteries, whereas sensitivity to NE was increased ( P < 0.05). Maximal acetylcholine-mediated dilatation was similar in WT and GHR KO mice, whereas the aorta of GHR KO mice showed an increased sensitivity to acetylcholine ( P < 0.05). In conclusion, loss of GHR leads to low BP and decreased levels of renin in plasma as well as increase in aortic eNOS expression. Furthermore, GHR deficiency causes functional and morphological changes in both heart and vasculature that are beyond the observed alterations in body size. These data suggest an important role for an intact GH/IGF-I axis in the maintenance of a normal cardiovascular system.
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| 4. |
- Lorentzon, Malin, 1976, et al.
(author)
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In vivo effects of myocardial creatine depletion on left ventricular function, morphology, and energy metabolism--consequences in acute myocardial infarction
- 2007
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In: Journal of cardiac failure. - 1532-8414. ; 13:3, s. 230-7
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Journal article (peer-reviewed)abstract
- BACKGROUND: The failing heart is characterized by disturbed myocardial energy metabolism and creatine (Cr) depletion. The aims of this study were to in vivo evaluate the effects of Cr depletion on: a) left ventricular (LV) function and morphology during rest and stress, b) LV energy metabolism, c) catecholamine in LV and plasma content, and d) incidence of malignant ventricular arrhythmias (MVA) during acute myocardial infarction (MI). METHODS AND RESULTS: Male rats weighing approximately 200 g were used. Two groups were studied: the rats treated with Cr analogue beta-guanidinopropionic acid (BGP) (n = 25) and controls (n = 23). BGP (1 M) was administered by subcutaneously implanted osmotic minipumps over 4 weeks. The rats (BGP n = 9, control n = 12) were than examined with transthoracic echocardiography at basal and at stress conditions induced by transesophageal pacing. In vivo (31)P magnetic resonance spectroscopy (MRS) was used for evaluation of myocardial energy status (BGP n = 7, control n = 12). (31)P MRS, echocardiography and high-performance liquid chromatography analysis of myocardial Cr, total adenine nucleotides and catecholamines in myocardium and plasma were performed on noninfarcted hearts. Myocardial infarction was induced in a subgroup of animals (BGP n = 15, control n = 15) by ligation of the left coronary artery resulting in a large ( approximately 50%) anterolateral MI and acute HF. A computerized electrocardiogram tracing was obtained continuously before induction of MI and up to 60 minutes postinfarction. Qualitative and quantitative variables of ventricular arrhythmias were analyzed using arrhythmia score. Body weight (BW) was lower (P < .01), whereas LV/BW was higher (P < .01) in the BGP group. Total myocardial Cr pool was decreased for at least 50% (P < .01) compared with the controls. There was no difference in total nucleotide pool. Phosphocreatine/adenosine-3-phosphate ratio was lower in the BGP group (P < .01). LV systolic function was disturbed during rest and stress (P < .05). Similarly, LV dimensions were increased in the BGP group (P < .05). Induction of acute MI resulted in markedly increased incidence of MVA and higher mortality in the BGP group (P < .01). CONCLUSIONS: Myocardial Cr depletion results in functional and structural LV alterations associated with lower myocardial energy reserve. Intact myocardial Cr metabolism is important for normal LV function during basal and stress conditions. Acute MI in the setting of myocardial Cr depletion leads to excessive mortality from ventricular arrhythmias and progressive heart failure.
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| 5. |
- Samuelsson, Anne-Maj, 1977, et al.
(author)
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Hyperinsulinemia: effect on cardiac mass/function, angiotensin II receptor expression, and insulin signaling pathways
- 2006
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In: Am J Physiol Heart Circ Physiol. ; 291:2
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Journal article (peer-reviewed)abstract
- To investigate the association between hyperinsulinemia and cardiac hypertrophy, we treated rats with insulin for 7 wk and assessed effects on myocardial growth, vascularization, and fibrosis in relation to the expression of angiotensin II receptors (AT-R). We also characterized insulin signaling pathways believed to promote myocyte growth and interact with proliferative responses mediated by G protein-coupled receptors, and we assessed myocardial insulin receptor substrate-1 (IRS-1) and p110 alpha catalytic and p85 regulatory subunits of phospatidylinositol 3 kinase (PI3K), Akt, MEK, ERK1/2, and S6 kinase-1 (S6K1). Left ventricular (LV) geometry and performance were evaluated echocardiographically. Insulin decreased AT1a-R mRNA expression but increased protein levels and increased AT2-R mRNA and protein levels and phosphorylation of IRS-1 (Ser374/Tyr989), MEK1/2 (Ser218/Ser222), ERK1/2 (Thr202/Tyr204), S6K1 (Thr421/Ser424/Thr389), Akt (Thr308/Thr308), and PI3K p110 alpha but not of p85 (Tyr508). Insulin increased LV mass and relative wall thickness and reduced stroke volume and cardiac output. Histochemical examination demonstrated myocyte hypertrophy and increases in interstitial fibrosis. Metoprolol plus insulin prevented the increase in relative wall thickness, decreased fibrosis, increased LV mass, and improved function seen with insulin alone. Thus our data demonstrate that chronic hyperinsulinemia decreases AT1a-to-AT2 ratio and increases MEK-ERK1/2 and S6K1 pathway activity related to hypertrophy. These changes might be crucial for increased cardiovascular growth and fibrosis and signs of impaired LV function.
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| 6. |
- Tivesten, Åsa, 1969, et al.
(author)
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Cardiac concentric remodelling induced by non-aromatizable (dihydro-)testosterone is antagonized by oestradiol in ovariectomized rats
- 2006
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In: J Endocrinol. ; 189:3, s. 485-91
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Journal article (peer-reviewed)abstract
- Previous studies on the cardiovascular effects of androgens in females, most of them using testosterone treatment, have yielded conflicting results. Testosterone is metabolized into oestradiol (E2) and dihydrotestosterone (DHT) within cardiovascular tissues. The aim of the present study was to explore the cardiovascular effects exerted by E2 and the non-aromatizable androgen DHT and to study possible interactions between these in female rats. Ovariectomized rats were treated with DHT, E2, or DHT+E2 for 6 weeks. DHT increased left-ventricular posterior wall thickness, assessed by echocardiography, whereas left-ventricular dimension, as well as total heart weight and calculated left-ventricular mass, were unchanged. DHT also increased the levels of insulin-like growth factor-I mRNA in the left ventricle. E2 abolished the effect of DHT on left-ventricular remodelling and insulin-like growth factor-I mRNA when the two treatments were given in combination. E2 also reduced androgen receptor mRNA levels in the heart. Neither E2 nor DHT changed blood pressure measured by telemetry. In conclusion, treatment with the endogenous non-aromatizable androgen DHT causes cardiac concentric remodelling in ovariectomized rats, possibly mediated by increased local levels of insulin-like growth factor-I. The effect of DHT on cardiac wall thickness was antagonized by E2, possibly through downregulation of cardiac androgen receptors. These mechanisms may be of importance for the concentric left-ventricular geometric pattern developing in women after menopause.
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