Early Pathophysiological Alterations in Experimental Cardiomyopathy: the Syrian Cardiomyopathic Hamster (original) (raw)
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Journal of Cardiac Failure, 2009
Background-Coronary vasospasms have been reported in the early stages of cardiomyopathy in the Syrian cardiomyopathic hamster (CM, BIO-TO2 strain). It has been proposed these alterations could lead to ischemic heart disease and heart failure. However, the cause of these coronary abnormalities has not been established. In this study, we evaluated coronary hemodynamic to assess the role of Ang-II, ROS, and NO in the development of these alterations in CM of 1, 2, and 6 months of age.
Altered vascular function in early stages of heart failure in hamsters
Journal of Cardiac Failure, 1997
Congestive heart failure is a clinical condition associated with alterations in the normal balance of neurohumoral agents and factors acting on the vascular wall. The etiology of this condition, however, remains largely undefined. To help elucidate the pathophysiology of this disease, vascular function and angiotensin-converting enzyme activity were evaluated in 2-month-old Syrian cardiomyopathic hamsters (SCHs) that had not yet developed heart failure. Age-matched normal hamsters were used as control hamsters. Methods and Results: Vascular function studies included determinations of contractile responses of aortic rings to 0.1 p~M angiotensin II and 0.1 FM norepinephrine. In addition, endothelial function was evaluated by the vasorelaxant action of acetylcholine on norepinephrine-precontracted aortic rings. The results indicate that the pressor effect of angiotensin II (0.1 IxM) was 35% greater in aortic rings from SCHs than that observed in control animals. This effect is specific for angiotensin II because the contraction induced by NE (0.1 ~M) was similar in both of these strains. Angiotensin-converting enzyme activity was threefold higher in aorta homogenates from SCHs but normal in plasma and heart tissue when compared with control hamsters. Aortic ring preparations from SCHs also exhibited endothelial dysfunction because the maximal relaxation elicited by 10 p~M acetylcholine was reduced 53%. Concentration-response curves with acetylcholine yielded ECs0 values that were threefold lower in SCHs (97.2 + 0.1 riM) than in control animals (286 + 7 nM). Indomethacin (1 ~M) increased the vasorelaxant effect of acetylcholine 28% in SCHs and shifted to the left the concentration-response curve of this agonist, suggesting an increased relaxation with the cyclooxygenase inhibitor. No effect of indomethacin on acetylcholineinduced relaxation was observed in control animals. Sodium nitroprusside induced similar relaxations in both control animals and SCHs, suggesting that the vascular smooth muscle response is normal in SCH. Conclusions: Altogether these results point to a state of enhanced vascular contractility in young SCHs that could predispose these animals to develop heart failure, the enhanced vascular contractility could result from increased activity of the local renin-angiotensin system, augmented vascular response to angiotensin II, reduced nitric oxide synthesis, and enhanced production of prostaglandins.
Anais Da Academia Brasileira De Ciencias, 2007
We investigated the morphologic and functional changes of infarcted rat hearts under a paradigm of angiotensinconverting enzyme inhibition. Myocardial infarction was induced by left coronary artery ligation and a control group (SHAM) underwent sham-operation. Infarcted rats received normal drinking water with (CAP group) or without (INF group) captopril. Functional assessment was performed by electro (ECG) and echocardiogram (ECHO) just before and 21 days after surgery. The ECG of INF and CAP showed similar values and resembled healed infarct after surgery. The most outstanding differences between INF and CAP were the prevention of the increase of P-wave and attenuation both in rightward deviation of the QRS axis and Q-wave amplitude in CAP compared with INF. The ECHO showed that captopril treatment improved the diastolic fi lling more than systolic performance. Cardiac dilatation and left congestive heart failure were observed only in INF. Both infarcted groups showed a scar tissue in the left ventricular wall, but the INF showed a higher scar area than CAP (49.7 ± 5.24 vs. 22.33 ± 6.19 respectively). These data suggest that the renin-angiotensin system induces morphologic and functional changes in post-infarcted rat hearts and which can be assessed by non-invasive exams.
Vascular Pharmacology, 2006
Recent studies indicate the presence of vascular alterations in 2-month-old Syrian cardiomyopathic hamsters (SCH). These alterations include enhanced angiotensin-converting enzyme (ACE) activity in the aorta, increased contractile response to angiotensin II and impaired vasorelaxation to acetylcholine in norepinephrine-precontracted aortic rings. The mechanisms leading to these vascular alterations are not known nor has their relationship to the cardiac abnormalities been established. We assessed the status of the cardiovascular system of 2-month-old hamsters first to establish if the observed vascular alterations are secondary to cardiac dysfunction, and second to examine the role of oxidative stress in the etiology of vascular dysfunction. Cardiac function parameters evaluated by echocardiography included stroke volume (SV), left ventricular enddiastolic volume (LVEDV), left ventricular fractional shortening (LVFS), ejection fraction (EF), cardiac output index (COI), heart rate (HR) and left ventricular posterior wall thickness (LVPWT). In addition, heart/body weight (heart/BW) ratios and systolic blood pressure were determined in normal hamsters and SCH. Our results indicated that systolic blood pressure increased 56% in SCH when compared to control animals ( P < 0.05). The increased blood pressure coexisted with normal COI, SV, LVEDV, LVPWT, LVFS, EF, HR and heart/BW ratios. NAD(P)H oxidase activity increased 77% in SCH compared to control animals ( P < 0.02). The increased oxidase activity was abolished by pre-treatment of animals with the angiotensin II type 1 receptor blocker losartan (25 mg/kg BW/day) for 10 days. Losartan also abolished the increased blood pressure observed at 2 months of age. The antioxidant N-acetylcysteine (NAC) abrogated the increased blood pressure when administered for 30 days to 1-month-old animals. Altogether, these findings suggest that the angiotensin II-dependent vascular abnormalities present in young cardiomyopathic hamsters are associated with oxidative stress and precede the echocardiographic abnormalities characteristic of heart failure. D
FEBS Letters, 1999
The N N-sarcoglycan (SG) gene is deleted in hamsters with hereditary cardiomyopathies. Immunological analyses of heart before, but not after, the progression of cardiomyopathy (CM) revealed that the BIO 14.6 strain, a model of hypertrophic CM, heterogeneously preserved K K-and Q Q-SG with loss of L L-and N N-SG. In contrast, the TO-2 strain, a model of dilated CM, did not show either SG. Furthermore, in vivo transfer of the full length N N-SG gene to TO-2 hearts expressed all four SGs. Thus, this age-and strain-dependent features suggest a more feasible setting for TO-2 than BIO 14.6 to verify both CM progression and the efficacy of gene therapy.
Proceedings of the National Academy of Sciences, 1997
Cardiomyopathy (CM) is a primary degenerative disease of myocardium and is traditionally categorized into hypertrophic and dilated CMs (HCM and DCM) according to its gross appearance. Cardiomyopathic hamster (CM hamster), a representative model of human hereditary CM, has HCM and DCM inbred sublines, both of which descend from the same ancestor. Herein we show that both HCM and DCM hamsters share a common defect in a gene for δ-sarcoglycan (δ-SG), the functional role of which is yet to be characterized. A breakpoint causing genomic deletion was found to be located at 6.1 kb 5′ upstream of the second exon of δ-SG gene, and its 5′ upstream region of more than 27.4 kb, including the authentic first exon of δ-SG gene, was deleted. This deletion included the major transcription initiation site, resulting in a deficiency of δ-SG transcripts with the consequent loss of δ-SG protein in all the CM hamsters, despite the fact that the protein coding region of δ-SG starting from the second exon...
Identification of the Syrian hamster cardiomyopathy gene
Human Molecular Genetics, 1997
The BIO14.6 hamster is a widely used model for autosomal recessive cardiomyopathy. These animals die prematurely from progressive myocardial necrosis and heart failure. The primary genetic defect leading to the cardiomyopathy is still unknown. Recently, a genetic linkage map localized the cardiomyopathy locus on hamster chromosome 9qa2.1-b1, excluding several candidate genes. We now demonstrate that the cardiomyopathy results from a mutation in the δ-sarcoglycan gene that maps to the disease locus. This mutation was completely coincident with the disease in backcross and F 2 pedigrees. This constitutes the first animal model identified for human sarcoglycan disorders.
Cellular and functional defects in a mouse model of heart failure
2000
Cellular and functional defects in a mouse model of heart failure. Am J Physiol Heart Circ Physiol 279: H3101-H3112, 2000.-Heart failure and dilated cardiomyopathy develop in mice that lack the muscle LIM protein (MLP) gene (MLP Ϫ/Ϫ ). The character and extent of the heart failure that occurs in MLP Ϫ/Ϫ mice were investigated using echocardiography and in vivo pressure-volume (P-V) loop measurements. P-V loop data were obtained with a new method for mice (sonomicrometry) using two pairs of orthogonal piezoelectric crystals implanted in the endocardial wall. Sonomicrometry revealed right-shifted P-V loops in MLP Ϫ/Ϫ mice, depressed systolic contractility, and additional evidence of heart failure. Cellular changes in MLP Ϫ/Ϫ mice were examined in isolated single cells using patch-clamp and confocal Ca 2ϩ concentration ([Ca 2ϩ ]) imaging techniques. This cellular investigation revealed unchanged Ca 2ϩ currents and Ca 2ϩ spark characteristics but decreased intracellular [Ca 2ϩ ] transients and contractile responses and a defect in excitation-contraction coupling. Normal cellular and whole heart function was restored in MLP Ϫ/Ϫ mice that express a cardiac-targeted transgene, which blocks the function of -adrenergic receptor (-AR) kinase-1 (ARK1). These data suggest that, despite the persistent stimulus to develop heart failure in MLP Ϫ/Ϫ mice (i.e., loss of the structural protein MLP), downregulation and desensitization of the -ARs may play a pivotal role in the pathogenesis. Furthermore, this work suggests that the inhibition of ARK1 action may prove an effective therapy for heart failure.