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At least 397 records · Page 22Linked to original sources
PubMed1998

Nitric oxide and endothelin in the development of cardiac allograft vasculopathy. Potential targets for therapeutic interventions.

Extensive research has been carried out in recent years to discover the potential risk factors contributing to cardiac allograft atherogenesis. Injury to endothelial cells has been regarded as an important early mechanism in the development of transplant atherosclerosis; it leads to the manifestation of epicardial and microvascular endothelial dysfunction and development of intimal hyperplasia. Moreover, continuous minor endothelial cell damage contributes to endothelial dysfunction which reflects one of the first measurable steps in the cascade of atherogenesis without macroscopic evidence of vascular lesions. The discovery of two important vasoactive substances nitric oxide (NO) and endothelin (ET) has brought new insights but also new unsolved questions regarding the mechanisms leading to atherosclerosis. To date it is known that both substances play a major role in both prevention and development of atherosclerosis. NO appears to be protective in low concentrations by inhibiting leukocyte and platelet activation/adherence and smooth muscle cell proliferation. Impaired endothelial NO production, as one cause of endothelial dysfunction may occur in early stages of atherosclerosis before macroscopic lesions are evident. In addition, increased endothelin release also results in endothelial dysfunction by inducing vasoconstriction; it promotes vascular lesion formation due to endothelial- and vascular smooth muscle cell proliferation. Direct and indirect manipulation of both the NO and ET signal transduction systems may provide novel preventive and therapeutic approaches for limiting transplant atherogenesis and to treat native atherosclerosis. This review summarizes important experimental and clinical evidence which points to nitric oxide and endothelin as potential therapeutic targets in the process of cardiac allograft vasculopathy.

Animals↗
PubMed2005

The keeshond defect in cardiac conotruncal development is oligogenic.

Earlier studies in the keeshond breed of dogs established that isolated conotruncal defects (CTDs) are a group of genetically and embryologically related cardiac malformations, including sub-clinical defects of the conal septum, conal ventricular septal defects, tetralogy of Fallot, and persistent truncus arteriosus. The same spectrum occurs in some human families. In both species, inheritance of non-syndromic CTDs is usually complex and multifactorial inheritance has been assumed. Previous studies in the keeshond suggested that susceptibility to CTD is an autosomal recessive trait, with alleles at modifying loci affecting severity. Here we report results of a genome-wide scan for CTD linked loci in a keeshond x beagle F1 backcross pedigree in which 46 of 101 offspring had CTDs. Two-point linkage analysis identified regions of suggestive linkage on each of three chromosomes CFA2, CFA9, and CFA15. No single locus accounted for segregation of CTDs in the pedigree, ruling out a single autosomal susceptibility locus. Multipoint analysis with Genehunter resulted in a corrected LOD score of 3.7 at the locus on CFA9 and supported linkage to the loci on CFA2 and CFA15 (LOD scores of 2.71 and 3.03). Genehunter Twolocus analysis suggested that CTD-predisposing alleles of these three loci are necessary, at least in pairs, to produce CTD. The canine CTD-linked chromosome regions are orthologous to human regions HSA5q11-13, HSA5q31, HSA17q11-24, and HSA4q31. We excluded from the linked regions in the dog, a number of genes known to have a role in the etiology of CTDs and predict that continuing studies will identify CTD-predisposing genes not previously recognized.

Animals↗
PubMed1989

[Passive diastolic properties of the left ventricle during development of cardiac hypertrophy].

Induced insufficiency of the aortal valve in rabbits is followed by gradual adaptation of the heart to volume load. In the period of developing hypertrophy, we studied the changes in the passive diastolic properties of the ventricle. By analyzing the passive relationship between the volume of the ventricular cavity and the intraventricular pressure, the stiffness of the ventricle, normalized ventricular stiffness, and myocardial stiffness were determined. On day 30 after inducing the volume verload, the stiffness constant of the ventricle was statistically significantly reduced, whereas the constant of normalized ventricular stiffness and the constant of myocardial stiffness were statistically significantly increased. The increased stiffness of the myocardium, which characterizes the volume verloaded, left ventricle in the period of developing hypertrophy, may represent one of the changes causing reversal of the adaptive response of the heart to hemodynamic verload after a certain period of time, gradually resulting in the development of the syndrome of heart failure.

Animals↗
PubMed1993

Basic mechanisms of cardiac gene expression.

Although the physiological properties of the myocardium and their dynamic character have been the focus of intense research during the past three decades, the biochemical and molecular correlates underlying cardiac development and performance have, until recently, remained poorly understood. The development of modern biology has provided the necessary tools to undertake the study of the mechanisms involved in cardiac development and to understand the basis for important clinical and experimental problems in cardiovascular physiology. Most of the gene encoding contractile proteins have been cloned and characterized. The availability of molecular probes and the ability to introduce genes into individual cell types and tissues of living animals are the most important breakthroughs of molecular and cell biology. This permits not only analysis of basic mechanisms of gene expression but has also significant practical applications for gene therapy. It is now possible to analyse the role of different regulatory gene sequences and identify their corresponding transactive factors. In addition direct gene injection makes it possible to study gene expression in a natural context, under conditions that are physiologically relevant and controllable.

Animals↗
PubMed1999

Transcription of the myogenic regulatory gene Mef2 in cardiac, somatic, and visceral muscle cell lineages is regulated by a Tinman-dependent core enhancer.

The MADS-box transcription factor MEF2 is expressed specifically in developing cardiac, somatic, and visceral muscle cell lineages during Drosophila embryogenesis and is required for myoblast differentiation and muscle morphogenesis. To define the mechanisms that regulate Mef2 transcription, we have analyzed the Mef2 upstream region for sequences sufficient to recapitulate the expression pattern of the gene in Drosophila embryos. Here we describe a complex enhancer located 5.8 kb upstream of the Drosophila Mef2 gene that controls transcription in cardial cells of the dorsal vessel, a subset of somatic muscle founder cells, and the visceral muscle cells. The core of this enhancer contains two evolutionarily conserved binding sites for the homeodomain protein Tinman (Tin), expressed in developing cardiac, somatic, and visceral muscle lineages. Both Tin binding sites are required for enhancer activity in all three muscle cell lineages. Whereas the 285-bp enhancer core alone is sufficient for expression in cardiac cells, expression in somatic founder cells and visceral muscle is dependent on the core enhancer plus unique flanking sequences that include an evolutionarily conserved E box. These results reveal an essential role for Tin in activation of Mef2 transcription in multiple myogenic lineages and demonstrate that transcriptional activity of Tin is dependent on combinatorial interactions with other factors unique to different muscle cell types.

Animals↗
PubMed1992

[A resuscitated case of sleep apnea syndrome with cardiac arrest].

A 71-year-old man was noted to habitually snore loudly at night and have a predisposition to somnolence during the daytime. While dozing during the day, he developed cardiac arrest at the time when snoring stopped, and was resuscitated. By means of a respiration monitor, he was diagnosed as having sleep apnea syndrome (SAS) with a combination of obstructive, central, and mixed type. However, neither respiratory insufficiency nor cardiac insufficiency was observed, and there were no abnormal findings on laboratory tests and bronchoscopy. SAS complicated by cardiac arrest is usually seen in cases with concomitant symptoms such as excessive obesity, hypertension, arrhythmia, right heart insufficiency, secondary polycythemia, or mental disorder. The present case abruptly developed cardiac arrest in the absence of such symptoms. This case therefore suggests the importance of screening tests using a respiration monitor during sleep in subjects who have a loud snore or a predisposition to somnolence during the daytime. Although treatment with UPPP alone had no noticeable effect, UPPP treatment combined with sleeping in the lateral position was effective in the present case. The efficacy rate of UPPP has been reported to be 50 to 60%. The early establishment of a method for precise evaluation of the site of obstruction as well as criteria for appropriate application of UPPP are urgently required.

Aged↗
PubMed2005

Prospective identification of cardiac progenitors by a novel single cell-based cardiomyocyte induction.

Dissection of cardiomyocyte differentiation process at the cellular level is indispensable in the research for cardiac development and regeneration. Previously, we have established an embryonic stem cell differentiation system that reproduces early vascular development from progenitor cells that express Flk1, a vascular endothelial growth factor receptor, by the combinatory application of 2-dimensional culture and flowcytometry. Here we show that cardiomyocytes can be successfully induced from a single Flk1+ cell on 2-dimensional culture, enabling the direct observation of differentiating cardiomyocytes and the prospective identification of cardiac progenitor potentials. Flk1+ cells could give rise to cardiomyocytes, as well as endothelial cells, from a single cell by the co-culture on OP9 stroma cells in a fusion-independent manner. Among the cell populations in intermediate stages from Flk1+ cells to cardiomyocytes, Flk1+/CXCR4+/vascular endothelial cadherin- cells were cardiac-specific progenitors at the single cell level. Noggin, a bone morphogenetic protein inhibitor, abolished cardiomyocyte differentiation by inhibiting the cardiac progenitor induction. However, wnt inhibitors Dkk-1 or Frizzled-8/Fc chimeric protein augmented, but wnt3a inhibited, cardiomyocyte differentiation. In vitro reproduction of cardiomyocyte differentiation process should be a potent tool for the cellular and molecular elucidation of cardiac development, which would provide various targets for cardiac regeneration.

Bone Morphogenetic Proteins↗
PubMed1988

Inhibition of leukotriene release in anaphylactic guinea-pig hearts by a 5-lipoxygenase inhibitor, CGS 8515.

1. Ovalbumen (100 micrograms)-induced coronary vasoconstriction and decrease in cardiac developed tension were studied in isolated perfused hearts from sensitized guinea-pigs. Leukotriene-like material released in the cardiac effluent was assayed against synthetic leukotriene C4 (LTC4). 2. LTC4 was released in a time-dependent fashion, and release was enhanced when hearts were challenged in the presence of indomethacin (2.8 microM). The release was maximal at 2-3 min and detectable for as long as 10 min following ovalbumen challenge. Immunoreactive (ir) thromboxane-B2 (TxB2) was also detected in cardiac effluent which had been partially purified using C18 Sep-Paks. 3. CGS 8515 (0.03-1.0 microM), an inhibitor of 5-lipoxygenase, dose-dependently inhibited ovalbumen-induced coronary vasoconstriction and leukotriene-C4 release. CGS 8515 inhibited ovalbumen-induced decreases in cardiac developed tension at 0.3 and 1.0 microM, but did not antagonize coronary vasoconstriction induced by synthetic LTC4. 4. The release of cyclo-oxygenase products following ovalbumen challenge was not inhibited by CGS 8515, but was markedly inhibited by indomethacin (2.8 microM) pretreatment. 5. We conclude that leukotrienes have a major role in guinea-pig cardiac anaphylaxis, and that CGS 8515 has a cardio-protective action. The results obtained in these experiments in vitro show that CGS 8515 is a potent and selective 5-lipoxygenase inhibitor.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed2006

Expression and function of alpha-smooth muscle actin during embryonic-stem-cell-derived cardiomyocyte differentiation.

Three alpha-muscle actin isoforms are sequentially expressed during in vivo cardiac development. alpha-Smooth muscle actin is first and transiently expressed, followed by alpha-skeletal and finally alpha-cardiac actin. The significance of these transitions in actin gene expression during myogenesis remains to be determined. To understand whether actin isoforms have specific functions during cardiac development and cardiomyocyte contractility, we have hampered alpha-smooth muscle and alpha-skeletal actin expression and organization during embryonic stem cell differentiation towards cardiomyocyte. We show that the sequence of actin isoform expression displays similar pattern in the in vitro model and in mouse heart embryogenesis. Treatment with an interfering fusion peptide containing the N-terminal sequence of alpha-smooth muscle actin during a time window preceding spontaneous beating, prevents proper cardiac sarcomyogenesis, whereas alpha-skeletal actin-fusion peptide has no effect. Knockdown of alpha-smooth muscle actin in embryonic stem cells using RNA interference also affects cardiac differentiation. The application of both fusion peptides on beating embryoid bodies impairs frequency. These results suggest specific functional activities for actin isoforms in cardiogenesis and cardiomyocyte contractility.

Actins↗
PubMed2002

Tetralogy of fallot and other congenital heart defects in Hey2 mutant mice.

Congenital malformations of the heart and circulatory system are the most common type of human birth defect. Recent studies have implicated the Notch signaling pathway in human cardiac development by demonstrating abnormalities of the JAG1 gene as the basis for Alagille syndrome and some cases of isolated tetralogy of Fallot or pulmonic stenosis. How the Notch pathway acts in cardiac development remains unknown, but the Hey family of basic helix-loop-helix (bHLH) transcription factors are candidates for mediating Notch signaling in the developing cardiovascular system. Here, we use gene targeting to determine the developmental functions of mouse Hey2, a Hey family member that is expressed during the embryonic development of the heart, arteries, and other organs. Homozygotes for the Hey2 mutant allele display a spectrum of cardiac malformations including ventricular septal defects, tetralogy of Fallot, and tricuspid atresia, defects that resemble those associated with mutations of human JAG1. These results establish Hey2 as an important regulator of cardiac morphogenesis and suggest a role for Hey2 in mediating or modulating Notch signaling in the developing heart.

Animals↗
PubMed2003

Mitochondrial K(ATP) channels and sarcoplasmic reticulum influence cardiac force development under anoxia in the Amazonian armored catfish Liposarcus pardalis.

The contribution of alterations in mitochondrial K(ATP) channel activity and the sarcoplasmic reticulum (SR) to anaerobic cardiac function in the anoxia tolerant armored catfish Liposarcus pardalis were assessed. K(ATP) channels contribute to hypoxic cardioprotection in mammals, but little is known of their action in more hypoxia tolerant animals. Anoxia resulted in a decrease in force in isometrically contracting ventricle strips to approximately 40% of the pre-anoxic level. This was maintained for at least 2 h. Upon reoxygenation, hearts recovered to the same level as control preparations. Treatment with 5-hydroxydecanoic acid (5HD), a specific mitochondrial K(ATP) blocker significantly increased force in preparations during anoxia and caused hypercontracture at reoxygenation. Ryanodine, a specific inhibitor of SR function, significantly increased force loss in ventricle preparations under anoxia. Results show that mitochondrial K(ATP) channel activity and SR function are important in anaerobic and post-anaerobic contractility in armored catfish heart.

Adenosine Triphosphate↗
PubMed2006

The NK homeodomain transcription factor Tinman is a direct activator of seven-up in the Drosophila dorsal vessel.

A complex regulatory cascade is required for normal cardiac development, and many aspects of this network are conserved from Drosophila to mammals. In Drosophila, the seven-up (svp) gene, an ortholog of the vertebrate chick ovalbumin upstream promoter transcription factors (COUP-TFI and II), is initially activated in the cardiac mesoderm and is subsequently restricted to cells forming the cardiac inflow tracts. Here, we investigate svp regulation in the developing cardiac tube. Using bioinformatics, we identify a 1007-bp enhancer of svp which recapitulates its entire expression in the embryonic heart and other mesodermal derivatives, and we show that this enhancer is initially activated by the NK homeodomain factor Tinman (Tin) via two conserved Tin binding sites. Mutation of the Tin binding sites significantly reduces enhancer activity both during normal development and in response to ectopic Tin. This is the first identification of an enhancer for the complex svp gene, demonstrating the effectiveness of bioinformatics tools in assisting in unraveling transcriptional regulatory networks. Our studies define a critical component of the svp regulatory cascade and place gene regulatory events in direct apposition to the formation of critical cardiac structures.

Animals↗
PubMed2005

Early reduction in left ventricular contractile reserve detected by dobutamine stress echo predicts high-dose chemotherapy-induced cardiac toxicity.

BACKGROUND: High-dose chemotherapy (HDC) is utilized in high-risk cancer patients. This type of treatment may induce cardiac toxicity which becomes clinically evident weeks or months after HDC. Hence, the possibility of early identification of patients who will develop cardiac impairment is strategic for its clinical implications. The aim of this study was to identify possible early changes of left ventricular contractile reserve (LVCR) in cancer patients undergoing HDC, as well as to evaluate the relevance of such changes as predictors of chemotherapy-induced cardiotoxicity. METHODS: In forty-nine female patients scheduled for HDC, due to poor-prognosis breast cancer, dobutamine stress echocardiography (DSE) was performed, before each of the three HDC cycles (C1, C2, C3), and 1, 4, and 7 months after the end of chemotherapy. According to rest left ventricular ejection fraction (LVEF) evaluated within 18 months after HDC (f-LVEF), patients were allocated to Group A (LVEF < 50% and >10 absolute units reduction) and to Group B (LVEF > or = 50%). RESULTS: Rest LVEF didn't show any significant difference between the two groups except at f-LVEF. Peak LVEF and LVCR significantly decreased in Group A only, starting from C3. At C3, a > or = 5 units fall in LVCR was found to be predictive for f-LVEF drop below 50%. CONCLUSIONS: In patients undergoing HDC, low-dose DSE allows the early identification of patients at a high risk of developing cardiac dysfunction.

Adult↗
PubMed2002

[New aspects of ICD therapy: from rhythm therapy to complex cardiac monitoring. Development of an implantable, ICD-assisted, intrathoracic 6-channel ECG for continuous monitoring of high infarct risk patients].

Implantable defibrillator systems (ICD) are therapy of choice for the treatment of life-threatening ventricular arrhythmias and in prevention of sudden cardiac death. In more than 80% of patients who receive an ICD, the underlying cardiac disease is a coronary heart disease. Since arrhythmogenic sudden cardiac death can be reliably prevented in these patients by the use of ICD technology, the cardiac prognosis for these patients is determined by the occurrence of myocardial ischemia and myocardial infarction, as well as from the heart failure which develops in consequence. An intrathoracic 6-channel ECG comparable to the standard surface ECG can be reconstructed by further technical development of the electrode configurations currently present in ICD systems. The importance of this development in early diagnosis of myocardial ischemias and myocardial infarction can hardly be adequately estimated at the moment. The chronic consequences of myocardial infarction can be completely prevented or at least greatly reduced by means of such diagnostics and inclusion of immediate initiation of effective, appropriate early therapeutic measures before more serious symptoms even occur. In the development and pilot studies thus far, it has been found that the intrathoracic 6-channel ECG which can be generated in the ICD is capable of reliably recognizing acute myocardial ischemia, irrespective of localization or extent earlier and better than the standard surface ECG. Continuous preventive ischemia monitoring using the implanted ICD thus appears possible in patients at risk of infarction.

Algorithms↗
PubMed1993

Molecular mechanisms of cardiac gene expression.

Although the physiological properties of the myocardium and their dynamic character have been the focus of intense research during the past three decades, the biochemical and molecular correlates underlying cardiac development and performance have, until recently, remained poorly understood. The development of modern cellular and molecular biology has provided the necessary tools to undertake the study of the mechanisms involved in cardiac development and to understand the basis for important clinical and experimental problems in cardiovascular physiology. Most of the gene encoding contractile proteins have been cloned and characterized. The availability of molecular probes and the ability to introduce genes into individual cell types and tissues of living animals, are the most important breakthroughs of molecular and cell biology. This permits not only to analyze basic mechanisms of gene expression but has also significant practical applications for gene therapy. It is now possible to analyze the role of different regulatory gene sequences and identify their corresponding trans-active factors. In addition, direct gene injection makes it possible to study gene expression in a natural context, under conditions that are physiologically relevant and controllable.

Animals↗
PubMed2005

Expression and regulation of mouse SERDIN1, a highly conserved cardiac-specific leucine-rich repeat protein.

Despite recent progress, the precise mechanisms responsible for vertebrate cardiac development are still enigmatic. Better understanding of cardiac biology and disease necessitates identification and analysis of a full spectrum of regulatory and structural proteins specific to the developing heart. By performing an in silico screen, we identified a cardiac-specific gene we named Serdin1. The Serdin1 gene is conserved, and the message is restricted to the heart in several vertebrate species, thus implicating Serdin1 as an important gene in cardiac development. In situ hybridization confirmed that the Serdin1 message is cardiac-specific in mice as early as embryonic day 8.5. Antibody staining demonstrated predominantly nuclear staining in immortalized cardiac cell lines (P19 and HL-1) and proliferating cultured cardiomyocytes, whereas in vivo SERDIN1 localizes to I bands of the sarcomere. Seven kilobases of the upstream regulatory sequence of Serdin1 is sufficient for cardiac-specific expression. Computer analysis revealed an 80-bp homologous region between the mouse and the human Serdin genes that contains GATA, SRF, and MEF sites. Cardiac specificity and localization patterns suggest that SERDIN1 is intimately integrated with the molecular pathways controlling cardiogenesis in vertebrates.

Amino Acid Sequence↗
PubMed1997

GATA4 transcription factor is required for ventral morphogenesis and heart tube formation.

Previous studies have suggested that the GATA4 transcription factor plays an important role in regulating mammalian cardiac development. In the studies described in this report we have used gene targeting to produce GATA4-deficient mice. Homozygous GATA4-deficient (GATA4-/-) mice died between 8.5 and 10.5 days post coitum (dpc). GATA4-/- embryos displayed severe defects in both rostral-to-caudal and lateral-to-ventral folding, which were reflected in a generalized disruption of the ventral body pattern. This resulted in the defective formation of an organized foregut and anterior intestinal pore, the failure to close both the amniotic cavity and yolk sac, and the uniform lack of a ventral pericardial cavity and heart tube. Analysis of cardiac development in the GATA4-/- mice demonstrated that these embryos developed splanchnic mesoderm, which differentiated into primitive cardiac myocytes that expressed contractile proteins. However, consistent with the observed defect in ventral morphogenesis, these GATA4-/- procardiomyocytes failed to migrate to the ventral midline to form a linear heart tube and instead formed aberrant cardiac structures in the anterior and dorsolateral regions of the embryo. The defect in ventral migration of the GATA4-/- procardiomyocytes was not cell intrinsic because GATA4-/- cardiac myocytes and endocardial cells populated the hearts of GATA4-/- -C57BL/6 chimeric mice. Taken together, these results demonstrated that GATA4 is not essential for the specification of the cardiac cell lineages. However, they define a critical role for GATA4 in regulating the rostral-to-caudal and lateral-to-ventral folding of the embryo that is needed for normal cardiac morphogenesis.

Animals↗