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At least 487 records · Page 27Linked to original sources
PubMed1999

Cellular localization of alpha3beta1 integrin isoforms in association with myofibrillogenesis during cardiac myocyte development in culture.

The cellular localization of alpha3beta1 integrin isoforms was examined in cultured neonatal myocytes at selected times during development using double immunofluorescence assays. The distribution of alpha3A subunits began as diffuse and patternless, but as the cells matured, the distribution assumed a sarcomeric banding pattern, and alpha3A appeared to be localized in costameres - sarcolemmal regions adjacent to the Z-disks. Alpha-actinin, a component of the Z-disk, was localized in the same intracellular regions. Temporal analysis of the incorporation of the alpha3A subunit and other myofibrillar proteins into sarcomeres revealed that alpha3A was integrated into sarcomeres following incorporation of alpha-actinin and myosin heavy chain (MHC) but prior to that of desmin. This suggests that alpha3A integrins are incorporated into a pre-existing myofibrillar structure, and it is unlikely that alpha3A integrins participate in the initial assembly of myofibrillar proteins. The alpha3B, beta1A and beta1D subunits were also localized in costameres, where they formed alpha3Abeta1A, alpha3Abeta1D and alpha3Bbeta1A heterodimers. The alpha3Bbeta1D heterodimer, however, was not found in cardiac myocytes. The antisera raised against the cytoplasmic domains of alpha3A, alpha3B, beta1A and beta1D caused disruption of sarcomere structure. Thus, the myofibril-extracellular matrix linkages mediated by isoforms of alpha3beta1 integrin may play a crucial role in the stabilization of myofibril assembly and in the maintenance of sarcomere structure. Co-immunoprecipitation experiments revealed that beta1A, but not beta1D, interacts with the Nck signaling protein, suggesting that Nck participates in downstream signaling triggered by beta1A and that the beta1A-mediated signaling pathway is distinct from that of beta1D.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Fog1 is required for cardiac looping in zebrafish.

To further our understanding of FOG gene function during cardiac development, we utilized zebrafish to examine FOG's role in the early steps of heart morphogenesis. We identified fragments of three fog genes in the zebrafish genomic database and isolated full-length coding sequences for each of these genes by using a combination of RT-PCR and 5'-RACE. One gene was similar to murine FOG-1 (fog1), while the remaining two were similar to murine FOG-2 (fog2a and fog2b). All Fog proteins were able to physically interact with GATA4 and function as transcriptional co-repressors. Whole-mount in situ hybridization revealed fog1 expression in the heart, the hematopoietic system, and the brain, while fog2a and fog2b expression was restricted to the brain. Injection of zebrafish embryos with a morpholino directed against fog1 resulted in embryos with a large pericardial effusion and an unlooped heart tube. This looping defect could be rescued by co-injection of mRNA encoding murine FOG-1, but not by mRNA encoding FOG-1 lacking the FOG repression motif. Taken together, these results demonstrate the importance of FOG proteins for zebrafish cardiac development and suggest a previously unappreciated role for FOG proteins in heart looping that is dependent on the FOG repression motif.

Animals↗
PubMed1988

Sympathetic changes during development of cardiac hypertrophy in aortic-constricted rats.

Cardiac hypertrophy is frequently associated with sympathetic changes that include increased myocardial norepinephrine turnover, depleted myocardial norepinephrine stores, decreased myocardial responses to sympathetic nerve stimulation, and elevated plasma catecholamines. To better understand these events mechanistically, the time course of each was assessed in rat hearts subjected to aortic constriction-induced pressure overload. There was no evidence of increased left ventricular norepinephrine turnover in abdominal aortic-constricted rats, when compared with sham-constricted animals, during the first 3 days postoperatively. Moreover, their turnover rate constants tended to be lower during this period, then increased significantly by day 7. Plasma catecholamines were increased and left ventricular norepinephrine stores were decreased only on day 7. Heart rate responses to maximal sympathetic nerve stimulation were significantly reduced on the third postoperative day. Thus the decrease in norepinephrine stores coincided with changes in left ventricular norepinephrine turnover and plasma catecholamines, whereas the reduction in heart rate responses did not. This pattern suggests an initial reflex decrease in myocardial sympathetic tone, followed by baroreceptor resetting, with an eventual increase in general sympathetic outflow. The period of increasing catecholamine stimulation occurred after a relative left ventricular hypertrophy had developed but before a significant increase in absolute left ventricular mass. Thus catecholamines may still importantly contribute to the hypertrophy seen in this model.

Animals↗
PubMed2003

Physical and functional interactions among AP-2 transcription factors, p300/CREB-binding protein, and CITED2.

The transcriptional co-activators and histone acetyltransferases p300/CREB-binding protein (CBP) interact with CITED2, a transcription factor AP-2 (TFAP2) co-activator. p300/CBP, CITED2, and TFAP2A are essential for normal neural tube and cardiac development. Here we show that p300 and CBP co-activate TFAP2A in the presence of CITED2. TFAP2A transcriptional activity was modestly impaired in p300(+/-) and CBP(+/-) mouse embryonic fibroblasts; this was rescued by ectopic expression of p300/CBP. p300, TFAP2A, and endogenous CITED2 could be co-immunoprecipitated from transfected U2-OS cells indicating that they can interact physically in vivo. CITED2 interacted with the dimerization domain of TFAP2C, which is highly conserved in TFAP2A/B. In mammalian two-hybrid experiments, full-length p300 and TFAP2A interacted only when CITED2 was co-transfected. N-terminal residues of TFAP2A, containing the transactivation domain, are both necessary and sufficient for interaction with p300, and this interaction was independent of CITED2. Consistent with this, N-terminal residues of TFAP2A were required for p300- and CITED2-dependent co-activation. A histone acetyltransferase-deficient p300 mutant (D1399Y) did not co-activate TFAP2A and did not affect the expression or cellular localization of TFAP2A or CITED2. In mammalian two-hybrid experiments p300D1399Y failed to interact with TFAP2A, explaining, at least in part, its failure to function as a co-activator. Our results suggest a model wherein interactions among TFAP2A, CITED2, and p300/CBP are necessary for TFAP2A-mediated transcriptional activation and for normal neural tube and cardiac development.

Animals↗
PubMed2006

Normal embryonic development and cardiac morphogenesis in mice with Wnt1-Cre-mediated deletion of connexin43.

Mice harboring a null mutation in the gap junction protein connexin43 (Cx43) die shortly after birth due to an obstruction of the right ventricular outflow tract of the heart. These hearts exhibit prominent pouches at the base of the pulmonary outlet, i.e., morphological abnormalities that were ascribed to Cx43-deficiency in neural crest cells. In order to examine the Cx43 expression pattern in neural crest cells and derived tissues and to test whether neural crest-specific deletion of Cx43 leads to the conotruncal defects seen in Cx43null mice, we ablated Cx43 using a Wnt1-Cre transgene. Deletion of Cx43 was complete and occurred in neural crest cells as well as in neural crest-derived tissues. Nevertheless, hearts of mice lacking Cx43 specifically in neural crest cells were indistinguishable from controls. Thus, the morphological heart abnormalities of Cx43 null mice are most likely not caused by lack of Cx43 in neural crest cells.

Animals↗
PubMed1988

Development of cardiac beat rate in early chick embryos is regulated by regional cues.

The mesoderm of each of the paired lateral heart-forming regions (HFRs) in the stage 5-7 chick embryo includes prospective conus (pre-C), ventricle (pre-V), and sinoatrial (pre-SA) cells, arranged in a rostrocaudal sequence (C-V-SA). With microsurgery we divided each HFR into three rostrocaudally arranged segments. After 24 hr of further incubation, each segment differentiated into a spontaneously beating vesicle of heart tissue to form a multiheart embryo. The cardiac vesicles in these embryos expressed left-right and rostrocaudal beat rate gradients: the left caudal pre-SA mesoderm produced tissue with the fastest beat rate of the six while the rostral vesicle formed from right pre-C was the slowest. In another operation, we prevented the HFRs from fusing in the midline by cutting through the anterior intestinal portal at stage 8, to produce cardia bifida (CB) embryos with an independently beating half-heart on each side. In these cases, the left half-heart of 87.2% of CB embryos beat faster than the right, confirming the left-right difference in intrinsic beat rate. To assess whether the future beat rate of each region is already determined in the st 5-7 HFR, we exchanged rectangular fragments of left pre-SA mesoderm and attached endoderm with right pre-C fragments to yield a left HFR with the sequence C-V-C and a right HFR with the sequence SA-V-SA. A CB operation was subsequently performed on these exchange embryos to prevent fusion of the lateral HFRs. Preconus mesoderm, transplanted to the pre-SA region, differentiated into tissue with a rapid beat rate, while pre-SA mesoderm relocated to the preconus region formed heart tissue with a slow spontaneous rate typical of the conus. In 73% of the exchange CB embryos, the left half-heart beat faster than the right, despite the origins of its mesoderm. The exchanged mesoderm developed a rate that was appropriate for its new location rather than the site of origin of the mesodermal fragment. In a third set of operations, we implanted a fragment of st 15 differentiated conus tissue into a site lateral to the left caudal HFR in st 5, 6, and 7 embryos, and subsequently performed CB operations on them. The implant caused the adjacent half-heart to develop with a slower beat rate than in unoperated or sham-operated controls.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2000

Expression of replication factor C 40-kDa subunit is down-regulated during neonatal development in rat ventricular myocardium.

During neonatal development, cardiac myocytes undergo a transition from hyperplastic to hypertrophic growth. Whether these cells are terminally differentiated and permanently withdrawn from the cell cycle shortly after birth is controversial. Nevertheless, the clinical observation that functionally significant myocardial regeneration has not been documented in cardiovascular disease or injury during adulthood seems to support the notion that the vast majority of cardiac myocytes do not proliferate once they differentiate. Regardless of the controversy, the elucidation on how mitosis is blocked in cardiac myocytes may facilitate development of new cardiovascular therapies, based on the regeneration of the adult myocardium. To better understand postnatal myocardial development, we performed suppression subtractive hybridization to isolate genes that are differentially expressed in day one or day seven postnatal rat ventricular myocardium. Here we report the down-regulated mRNA expression of the 40-kDa subunit of replication factor C (RFC p40 or RFC2), which is an essential processive factor for proliferating cellular nuclear antigen-dependent DNA replication during neonatal myocardial development.

Age Factors↗
PubMed2000

Role of troponin I isoform switching in determining the pH sensitivity of Ca(2+) regulation in developing rabbit cardiac muscle.

Skinned muscle fibers prepared from fetal rabbit heart (28 days of gestation) showed a marked resistance to acidic pH in the Ca(2+) regulation of force generation, compared to the fibers prepared from adult heart. SDS-PAGE and immunoblot analysis showed that the slow skeletal troponin I was predominantly expressed in the fetal cardiac muscle, while the cardiac isoform was predominantly expressed in the adult cardiac muscle. Direct exchange of purified slow skeletal and cardiac troponin I isoforms into these skinned muscle fibers revealed that cardiac troponin I made the Ca(2+) regulation of contraction sensitive to acidic pH just as in the adult fibers, whereas slow skeletal troponin I made the Ca(2+) regulation of contraction resistant to acidic pH just as in the fetal fibers. These results demonstrate that the troponin I isoform switching accounts fully for the change in the pH dependence of Ca(2+) regulation of contraction in developmental cardiac muscle.

Aging↗
PubMed1995

Sympathetic innervation modulates the expression of angiotensin II receptors in embryonic rat heart grafted in oculo.

Angiotensin II acts as a cardiac growth factor, and causes both inotropic and chronotropic changes within the heart. In the present study, we used an in oculo model system to examine the effects of sympathetic innervation on the density of cardiac angiotensin II receptors. Quantitative autoradiography was used to determine the density of angiotensin II receptors in embryonic rat hearts grafted into either sympathetically innervated or sympathetically denervated eye chambers of adult host rats. The density of specific binding to angiotensin II receptors was nearly three-fold higher in sympathetically non-innervated compared to sympathetically innervated heart grafts (30.8 +/- 4.2 v 11.5 +/- 3.2 fmol/mg protein). Specific binding to angiotensin II receptors in heart grafts was displaced by addition of the AT1 receptor antagonist losartan, but not by addition of the AT2 receptor competitor PD 123177. Thus, only AT1 receptors were present in sympathetically innervated and sympathetically non-innervated embryonic rat hearts grafted in oculo. We conclude that changes in sympathetic innervation caused changes in the density of cardiac angiotensin II receptors in the present study. Our results may have implications for growth and function not only during cardiac development, but also during cardiac disease.

Age Factors↗
PubMed1997

Anthracyclines enhance tension development in cardiac muscle by direct interaction with the contractile system.

Anthracyclines are highly effective anticancer agents which induce a well described but incompletely understood cardiac toxicity. In this study, a direct action of several anthracyclines on the force generating mechanism of heart muscle preparations is described. To allow discrimination between membrane related effects and a direct action of anthracyclines on the actin-myosin contractile system, both inner and outer membranes of cardiac fibres were permeabilized. All anthracyclines tested in this study [doxorubicin (Dox), epirubicin, daunorubicin and idarubicin] showed positive inotropic actions. Dox and epirubicin, which are considered the most cardiotoxic drugs of the anthracycline family, significantly increased the maximal calcium activated tension by 33% (n = 8, P < 0.01) and by 26% (n = 8, P < 0.01) respectively. Daunorubicin and idarubicin increased the maximal tension by 12% and 9% respectively (P = n.s.). Other chemotherapeutic drugs (Taxol and 5-FU) had no effect on maximal tension. To elucidate the mechanism behind this Dox-induced increase in maximal tension, calcium sensitivity curves were measured and rigor experiments were performed. A small but significant increase in pCa50 value (+0.14 +/- 0.03, P < 0.05) was observed only after incubation with 20 microM Dox. Dox acted during the transition to force generating cross-bridges as reflected by the significant increase in rigor tension (12%, P < 0.05) after preincubation of cardiac fibres with Dox. Cycling of cross-bridges is a prerequisite for Dox to increase tension because no effect on tension was seen after Dox was added to fibres in an established rigor. In summary, anthracyclines increased the maximal tension in cardiac muscle fibres by direct interaction with the actin-myosin cross-bridges. Changes in calcium sensitivity are unlikely to contribute to the observed increase in maximal tension. The rise in tension as is seen in this experimental set-up may contribute to destruction of the contractile machinery of cardiac muscle. In agreement with this hypothesis is the observation that the more cardiotoxic anthracyclines induced the largest increase in maximal tension of the cardiac fibres.

Animals↗
PubMed1981

The effects of the bradycardia-producing compound alinidine on action potentials and tension development in cardiac fibres.

Alinidine (ST 567, N-Allyl-Clonidine) exerted concentration-dependent negative chronotropic effects in isolated, spontaneously-beating sinus node cells and Purkinje fibres of guinea pigs and in ventricular strips of chick embryonic myocardium. Reduction of beat frequency by 30% was found after addition of 8.6 mumol/l alinidine in the former. A chronotropic effect was not seen during Ba2+-induced automaticity or triggered activity in guinea-pig papillary muscles and in enzymatically disaggregated cells of embryonic chick myocardium, which lose the beta-adrenoceptor responsiveness of the intact embryonic ventricle. In contrast to alinidine, D600 showed very pronounced and quinidine minor negative chronotropic effects in these latter experiments. Reduction of excitability, rate of rise of the action potential and velocity of repolarization as well as prolongation of the refractory period were seen after applications of very high concentrations of alinidine (285 mumol/l). In electrically-driven atria isometric peak tension was only slightly changed (increased by 85.5 mumol/l, decreased by 285 mumol/l) but it was reduced (to 36.8%) by alinidine (85.5 mumol/l) in papillary muscles. Both in atria and in papillary muscles, the maximum rate of rise of the action potential was unchanged by alinidine up to 85.5 mumol/l and the slight reduction following 285 mumol/l alinidine application was independent of the rate of stimulation. The present findings confirm the selectivity of the bradycardic effects of alinidine which has a main mode of action different to that of membrane stabilizing compounds or inhibitors of the slow inward current.

Action Potentials↗
PubMed1981

2,4,5-T effects on cardiac and serum lactic dehydrogenase (LDH) and creatine kinase (CK) isozymes. II. Neonatal enzyme activities and isozyme profiles.

Neonates from CD-1 mice, which were treated during gestation with 100 mg/kg of 2,4,5-T, were studied from day 1 to 30 postpartum (pp) for effects on cardiac development by determining total cardiac activities and isozyme profiles of LDH and CK. On day 1pp, the total activities and isozyme profiles of LDH of the neonatal hearts were normal. During the developmental period of day 7 through 15, changes were noted in the developmental pattern of LDH isozymes some of which continued to day 30. The CK isozyme profile on day 1pp showed a significant change and changes continued throughout the lactational period. During this period, the normal developmental isozyme patterns of LDH and CK were altered by prenatal exposure to 2,4,5-T suggesting metabolic derangement or pathological changes in the neonatal heart.

2,4,5-Trichlorophenoxyacetic Acid↗
PubMed1985

Recent developments of cardiac digital radiography.

Digitization in cardiovascular radiology is on the verge of its realization. Since its introduction digital subtraction angiography (DSA) is gradually replacing conventional angiography in several areas of the body. The initial tendency to avoid the arterial catheterization by intravenous injection is somewhat reversed in favor of smaller intraarterial amounts of contrast medium injected through smaller catheters at reduced rates. However, left ventriculography by intravenous route has gained widespread acceptance at rest and with exercise: motion artifacts are less crucial for ventriculography than for small arteries, in which the same motion artifacts cause a more important relative deterioration of the image, so that it has to be corrected by pixel shift. DSA is only the first step towards functional imaging, where time and other parameters are condensed in one single color coded picture. Biharmonic Fourier analysis for quantitative analysis of regional left ventricular contraction and relaxation and digital coronary radiography for evaluation of contrast progression in the coronary circulation are two areas of cardiology where parametric imaging can help to detect functional abnormalities, especially in coronary heart disease.

Arteries↗
PubMedDate not supplied

A biphasic change in contractile proteins during the development of cardiac hypertrophy in pigs.

A non-failing hypertrophy of the left ventricle was produced in the pig heart by supravalvular banding of aorta for 4, 8 and 12 weeks and the myosin and myofibrillar adenosine triphosphatase activities were measured. A significant increase in myosin Ca2+-ATPase activity was seen at 4 weeks of hypertrophy, but at 8 and 12 weeks this activity was significantly decreased compared to sham control. Similar changes were also seen in actin-activated myosin ATPase activities at 4, 8 and 12 weeks of hypertrophy. There were no changes in the K+- and NH4+-EDTA-stimulated ATPAse activities of myosin. Basal ATPase activities of myofibrils were decreased at 4 and 8 weeks of hypertrophy and there was no change in this activity at 12 weeks of hypertrophy. Ca2+ stimulated ATPase activity of myofibrils was significantly increased at 4 weeks, normal at 8 weeks and significantly reduced at 12 weeks of hypertrophy. The changes in ATPase activities were not due to any alterations of proteins by high concentrations of salts during the purification of myosin. The non-hypertrophied right ventricle from the banded animals did not show any change in the basal or Ca2+ stimulated myofibrillar ATPase activities. It is suggested that hypertrophy of the myocardium is accompanied by specific changes in the enzyme activities of the contractile proteins and the biphasic responses may correlate with the functional state of the myocardium subjected to a chronic increase in pressure.

Adenosine Triphosphatases↗
PubMed2006

Carcinoid heart disease.

Progress in the medical and surgical management of patients with carcinoid disease has resulted in improved symptoms and survival. Carcinoid heart disease remains a major cause of morbidity and mortality among patients with malignant carcinoid syndrome. Limited medical treatment options are available for patients with symptomatic carcinoid heart disease. At the Mayo Clinic (Rochester, MN), we have taken an aggressive approach to severe valvular dysfunction from carcinoid heart disease. Patients with severe carcinoid heart disease currently are referred for cardiac operation when they develop cardiac symptoms, ventricular dysfunction, or (rarely) in anticipation of hepatic surgery. Surgical outcome depends on patient age and functional class at the time of cardiac surgery. Despite metastatic disease that limits longevity, cardiac surgical survivors usually demonstrate dramatic improvement in functional capacity. Cardiac surgery should be considered early for patients with symptomatic carcinoid heart disease and controlled carcinoid symptoms. An experienced medical, surgical, and anesthetic team approach to the patient with carcinoid heart disease is critical in order to provide state of the art management.

Bioprosthesis↗