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PubMed1997

Immunolocalization and heart levels of GRP94 in the mouse during post-implantation development.

Glucose-regulated proteins (GRPs), which belong to the highly conserved family of stress proteins, are resident to the endoplasmic reticulum and function as molecular chaperones. Heat shock proteins have been shown to be developmentally regulated, but little work has been done to investigate the expression of GRPs during embryogenesis. Therefore, this study examined the distribution of GRP94 within mouse embryos during the period of organogenesis and characterized levels of GRP94 within the developing heart during organogenesis and late fetal stages. Our results demonstrate that the GRP94 protein is constitutively expressed within mouse embryos during early stages of organogenesis and is localized particularly within the developing heart, neuroepithelium, and surface ectoderm tissues. Positive staining for GRP94 remains within developing heart tissues throughout organogenesis and is found primarily within the atrial and ventricular myocardial cells. Western blot analysis of GRP94 expression demonstrates a significantly higher level of GRP94 in embryonic hearts during early stages of organogenesis than in later stages of organogenesis or the fetal period. These results demonstrate that the stress protein GRP94 is constitutively expressed within specific tissues during post-implantation mouse development and suggest that GRPs may play an important role in the process of myocardial cell differentiation and heart development.

Animals↗
PubMed2000

Transient expression of NMDA receptor subunit NR2B in the developing rat heart.

NMDA receptors represent a subtype of the ionotropic glutamate receptor family, comprising three classes of subunits (NR1, NR2A-D, NR3), which exhibit distinct patterns of regional and developmental expression in the CNS. Recently, some NMDA receptor subunits have also been described in adult extraneuronal tissues and keratinocytes. However, their developmental expression patterns are currently unknown. With use of RT-PCR and western blot analysis, the expression of NMDA receptor subunit NR2B was investigated in the developing rat heart. NR2B mRNA and protein were detected in heart tissue of rats from embryonic day 14 until postnatal day 21 but disappeared 10 weeks after birth. In contrast, no NMDA receptor subunit NR1, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor subunit GluR2, or anchoring postsynaptic density protein-95 could be detected in rat heart at any developmental stage. Confocal microscopy of cultured cardiac myocytes (CMs) from neonatal rats revealed distinct NR2B staining mainly of intracellular structures. However, no functional NMDA receptor could be detected on CMs by whole-cell recordings. In conclusion, high concentrations of NR2B protein can be detected in early rat heart development, but its function still remains elusive.

Animals↗
PubMed1999

The expression of Jagged1 in the developing mammalian heart correlates with cardiovascular disease in Alagille syndrome.

The establishment of the cardiovascular system represents an early, critical event essential for normal embryonic development, and defects in cardiovascular development are a frequent cause of both in utero and neonatal demise. Congenital cardio-vascular malformations, the most frequent birth defect, can occur as isolated events, but are frequently presented clinically within the context of a constellation of defects that involve multiple organs and that define a specific syndrome. In addition, defects can be a primary effect of gene mutations or result from secondary effects of altered cardiac physiology. Alagille syndrome (AGS) is an autosomal dominant disorder characterized by developmental abnormalities of the heart, liver, eye, skeleton and kidney. Congenital heart defects, the majority of which affect the right-sided or pulmonary circulation, contribute significantly to mortality in AGS patients. Recently, mutations in Jagged1 ( JAG1 ), a conserved gene of the Notch intercellular signaling pathway, have been found to cause AGS. In order to begin to delineate the role of JAG1 in normal heart development we have studied the expression pattern of JAG1 in both the murine and human embryonic heart and vascular system. Here, we demonstrate that JAG1 is expressed in the developing heart and multiple associated vascular structures in a pattern that correlates with the congenital cardiovascular defects observed in AGS. These data are consistent with an important role for JAG1 and Notch signaling in early mammalian cardiac development.

Alagille Syndrome↗
PubMed1999

Lifetime risk of developing coronary heart disease.

BACKGROUND: The lifetime risk of developing coronary heart disease has not been estimated in a general population. We investigated the lifetime risks of initial coronary events at different ages. METHODS: We assessed data for 7733 participants in the Framingham Heart Study, who had been examined at least once at age 40-94 years between 1971 and 1975, found to be free of coronary heart disease, and then followed up. We estimated the lifetime risks of coronary heart disease (angina pectoris, coronary insufficiency, myocardial infarction, or death from coronary heart disease) by multiple-decrement life-table methods. FINDINGS: The 7733 patients were followed up for a total of 109,948 person-years. Overall, 1157 participants developed coronary heart disease. 1312 died from non-coronary heart disease causes. Lifetime risk of coronary heart disease at age 40 years was 48.6% (95% CI 45.8-51.3) for men and 31.7% (29.2-34.2) for women. At age 70 years, lifetime risk was 34.9% (31.2-38.7) for men and 24.2% (21.4-27.0) for women. After we excluded isolated angina pectoris as an initial event, the lifetime risk of coronary artery disease events at age 40 years was 42.4% for men and 24.9% for women. INTERPRETATION: Lifetime risk at age 40 years is one in two for men and one in three for women. Even at age 70 years it is one in three for men and one in four for women. This knowledge may promote efforts in education, screening, and treatment for prevention of coronary heart disease in younger and older patients.

Adult↗
PubMed1988

Proliferation and biosynthetic activities of myocytes from conductive system and working myocardium of the developing mouse heart. Light microscopic autoradiographic study.

Incorporation of 3H-thymidine, 3H-uridine and 3H-leucine into myocytes and their mitotic activity have been investigated in different compartments of the mouse heart conductive system (CS) and working myocardium (WM) at pre- and postnatal stages of development. On 15th and 18th d of embryogenesis, 3H-thymidine pulse and cumulative labelling indices (LI) of myocytes in the sinoatrial node (SAN), atrioventricular node (AVN) and His bundle (HB) were found to be 4 to 6 times lower than in WM (0.001 less than or equal to P less than or equal to 0.01). On 3rd to 9th d after birth LI remained decreased (0.001 less than or equal to P less than or equal to 0.05) in SAN while replicative activity of myocytes in AVN and HB approached that of both ventricular and atrial WM. Since 13th d after birth LI did not exceed 1% in all the compartments studied. In the prenatal period LI in SAN were higher than in AVN P less than or equal to 0.01), whereas in the postnatal one it was just the opposite (0.001 less than or equal to P less than or equal to 0.05). During cardiogenesis change of mitotic indices in WM and CS correlates with that of LI. Duration of cell cycle and its periods (G2, G2 + 1/2 M, S) estimated by curves of labeled mitoses, double-labelling technique with 14C-thymidine and 3H-thymidine and label "dilution" method differ slightly in myocytes from WM and CS. The latter incorporate 3H-uridine much less intensively at most stages of heart development compared with WM. At perinatal stages of cardiogenesis 3H-leucine labels CS myocytes somewhat weaker than WM ones until 8th d after birth when the labelling intensities in all cell types become similar. It can be concluded that on the whole CS myocytes from the developing mouse heart appear to be less active than those of WM concerning replication, transcription, and translation processes.

Aging↗
PubMed2002

Development of heart failure and congenital septal defects in mice lacking endothelial nitric oxide synthase.

BACKGROUND: Nitric oxide (NO) produced by endothelial NO synthase (eNOS) plays an important role in the regulation of cell growth, apoptosis, and tissue perfusion. Recent studies showed that mice deficient in eNOS developed abnormal aortic bicuspid valves. The aim of the present study was to additionally investigate the role of eNOS in heart development. METHODS AND RESULTS: We examined postnatal mortality, cardiac function, and septum defects in eNOS(-/-), eNOS(+/-), and wild-type mice. Postnatal mortality was significantly increased in eNOS(-/-) (85.1%) and eNOS(+/-) (38.3%) compared with wild-type mice (13.3%, P<0.001). Postmortem examination found severe pulmonary congestion with focal alveolar edema in mice deficient in eNOS. Heart shortening determined by ultrasound crystals was significantly decreased in eNOS(-/-) compared with wild-type mice (P<0.05). Congenital atrial and ventricular septal defects were found in neonatal hearts. The incidence of atrial or ventricular septal defects was significantly increased in eNOS(-/-) (75%) and eNOS(+/-) (32.4%) neonates compared with those of the wild-type mice (4.9%). At embryonic days 12.5 and 15.5, cardiomyocyte apoptosis and myocardial caspase-3 activity were increased in the myocardium of eNOS(-/-) compared with wild-type embryos (P<0.01), and increases in apoptosis persisted to neonatal stage in eNOS(-/-) mice. CONCLUSIONS: Deficiency in eNOS results in heart failure and congenital septal defects during cardiac development, which is associated with increases in cardiomyocyte apoptosis. Our data demonstrate that eNOS plays an important role in normal heart development.

Animals↗
PubMed1999

Myocardial osteopontin expression coincides with the development of heart failure.

To identify genes that are differentially expressed during the transition from compensated hypertrophy to failure, myocardial mRNA from spontaneously hypertensive rats (SHR) with heart failure (SHR-F) was compared with that from age-matched SHR with compensated hypertrophy (SHR-NF) and normotensive Wistar-Kyoto rats (WKY) by differential display reverse transcriptase-polymerase chain reaction. Characterization of a transcript differentially expressed in SHR-F yielded a cDNA with homology to the extracellular matrix protein osteopontin. Northern analysis showed low levels of osteopontin mRNA in left ventricular myocardium from WKY and SHR-NF but a markedly increased (approximately 10-fold) level in SHR-F. In myocardium from WKY and SHR-NF, in situ hybridization showed only scant osteopontin mRNA, primarily in arteriolar cells. In SHR-F, in situ hybridization revealed abundant expression of osteopontin mRNA, primarily in nonmyocytes in the interstitial and perivascular space. Similar findings for osteopontin protein were observed in the midwall region of myocardium from the SHR-F group. Consistent with the findings in SHR, osteopontin mRNA was minimally increased (approximately 1.9-fold) in left ventricular myocardium from nonfailing aortic-banded rats with pressure-overload hypertrophy but was markedly increased (approximately 8-fold) in banded rats with failure. Treatment with captopril starting before or after the onset of failure in the SHR reduced the increase in left ventricular osteopontin mRNA levels. Thus, osteopontin expression is markedly increased in the heart coincident with the development of heart failure. The source of osteopontin in SHR-F is primarily nonmyocytes, and its induction is inhibited by an angiotensin-converting enzyme inhibitor, suggesting a role for angiotensin II. Given the known biological activities of osteopontin, including cell adhesion and regulation of inducible nitric oxide synthase gene expression, these data suggest that it could play a role in the pathophysiology of heart failure.

Animals↗
PubMedDate not supplied

Acetylcholine content in the brain and heart of developing rats.

Acetylcholine content in the brain and heart of developing rats. Acta Physiol. Pol. 1975, 26 (1): 41-44. The content of acetylcholine was determined in four parts of the brain and in the heart of developing rats. It was found that changes in acetylcholine level were not parallel in the examined brain stuctures and in the heart in the time period from birth to 18 months of age of the rats.

Acetylcholine↗
PubMed1997

Identification and characterization of the zeta-opioid receptor in developing rat heart.

Opioid growth factor (OGF; [Met5]enkephalin) inhibits DNA synthesis of epicardial and myocardial cells in the neonatal rat heart in a receptor-mediated fashion. Ligand binding assays using newborn rat heart and [3H][Met5]enkephalin were performed to characterize the receptor responsible for the cell replicative effects of OGF in developing heart. Specific and saturable binding was detected, and Scatchard analysis revealed that the data were consistent for a single binding site with a binding affinity of 6.8 +/- 0.3 nM and a binding capacity of 21.8 +/- 1.9 fmol/mg protein. Subcellular fractionation studies revealed that binding was restricted to the nuclear fraction. Competition experiments showed that cold [Met5]enkephalin was the most effective ligand at displacing [3H][Met5]enkephalin. Binding was recorded on gestation days 18 and 20, reached its highest level at birth, and steadily decreased from postnatal days 1 to 15; binding at days 21 and 35 and in adults was negligible. The function, pharmacological and biochemical characteristics, distribution, and subcellular location of this OGF receptor in developing mammalian heart are consistent with the zeta-opioid receptor.

Animals↗
PubMed2006

A common progenitor at the heart of development.

Formation of the heart requires the coordinated functions of cardiac myocytes, smooth muscle cells, endothelial cells, and connective tissue elements. Several recent studies now reveal that these different cell types arise from a common progenitor (). These findings raise interesting questions about the lineage relationships of cardiovascular progenitor cell populations and suggest possibilities for cardiac repair in both congenital and acquired heart disease.

Animals↗
PubMed1993

Contraction of developing avian heart muscle.

1. Developmental changes in contraction of chick heart show strong similarities with those of the mammalian myocardium. 2. Normalized twitch force of intact trabeculae from chick left ventricle increases most markedly during the 3-day period around the time of hatching. 3. At any age, elevation of extracellular [Ca2+] to 10-20 mM increases twitch force to a maximum. 4. Studies using membrane-free ("skinned") trabeculae demonstrate that the developmental increase in twitch force is paralleled by an increase in the maximal contractile capability of the muscle, that is probably due to proliferation of contractile proteins. 5. At all ages studied, maximal twitch force of intact trabeculae at 10-20 mM extracellular [Ca2+] is similar to maximal Ca(2+)-activated force of the trabeculae after skinning. 6. Calcium sensitivity of the contractile apparatus in chick heart decreases with development in parallel with isoform switching in troponin T. 7. The depressant effect of acidosis on calcium sensitivity of the contractile apparatus increases with development in parallel with isoform switching in troponin I. 8. As in mammalian heart, both acidosis and inorganic phosphate (Pi) depress force generation by the contractile machinery of chick heart.

Animals↗
PubMed1998

Differences in heart phospholipids in two inbred rat strains differing in sensitivity to the development of heart lesions.

The content of phospholipids and their fatty acid composition were followed in the hearts of two inbred strains of rats: IR, resistant against the development of isoprenaline-induced myocardial lesions and IS, sensitive to their development. In the hearts of rats of the resistant strain, a lower content of phosphatidylcholine and its plasmalogen fraction was found compared to IS rats. The total amount of phospholipids was only insignificantly lower in IR rats. Greater differences were found in individual fatty acids. The most important finding concerned lower arachidonic acid and higher linoleic acid content in heart phospholipids of IR rats. These differences were exactly opposite to changes reported in the literature in animals known to have a higher resistance against myocardial damage due to various interventions. Our results do not support the hypothesis claiming the importance of changes in phospholipids and their FA composition for the resistance of the heart against the development of necrotic lesions.

Animals↗
PubMed1990

Spatial distribution of "tissue-specific" antigens in the developing human heart and skeletal muscle. I. An immunohistochemical analysis of creatine kinase isoenzyme expression patterns.

Using monoclonal antibodies against the M and B subunit isoforms of creatine kinase (CK) we have investigated their distribution in developing human skeletal and cardiac muscle immunohistochemically. It is demonstrated that in skeletal muscle, a switch from CK-B to CK-M takes place around the week 8 of development, whereas in the developing heart, CK-M is the predominant isoform from the earliest stage examined onward (i.e., 4 1/2 weeks of development). In all hearts examined, local differences in concentration of the CK isoforms are observed. The CK-M expression in the developing outflow tract (OFT) and conduction system is described in detail. Between the weeks 5 and 7 of development, the distal portion of the OFT is characterized by low CK-M expression, whereas around the week 8-10 of development the myocardium around the developing semilunar valves in the OFT expresses a very high level of CK-M. At all stages examined, a relatively low CK-M level is observed in those regions in which the "slow" components of the conduction system do develop (e.g., the sinoatrial junction and atrioventricular junction), whereas a relatively high concentration of CK-M is observed in those areas that are destined to become the "fast" components, i.e., the subendocardial myocardium of the ventricles. The high expression of CK-M in the developing "fast components" of the conduction system contrasts with the relatively low expression of CK-M in the force-producing myocardium of the interventricular septum and free ventricular wall.

Creatine Kinase↗
PubMed2004

Neurotrophin-3 and TrkC are expressed in the outflow tract of the developing chicken heart.

Transcripts encoding trkC and full-length (catalytic) TrkC receptors were detected in the outflow tract of the chicken heart during early development (stage 17; embryonic day [E] 2.5) before the start of septation. Expression of trkC mRNA persisted through early septation (stage 25, E4.5-E5) but was no longer evident by the end of septation (stage 34, E8). Neurotrophin-3 (NT-3) mRNA was also shown to be present in the outflow tract throughout cardiac development. Quail-chick chimeras were used to confirm that cardiac neural crest cells were not present in the outflow tract at stage 17 (E2.5). Our results show that NT-3 interacts with cells in the outflow tract that are not of neural crest origin. This finding indicates that, in addition to effects on neural crest cells, NT-3 may be important for cardiac development due to its interaction with cells in the outflow tract such as those arising from the secondary heart field.

Animals↗
PubMedDate not supplied

Chronic in vivo evaluation of an electrohydraulic total artificial heart.

Development of the Abiomed total artificial heart (TAH) designed for human use is progressing. Implant durations of longer than 60 days have been achieved in calves. The device consists of blood pumps, valves, and a hydraulic atrial flow balancing chamber fabricated from polyetherurethane. The energy converter, a centrifugal hydraulic pump with a rotary fluid switching valve, is positioned between the blood pumps. In two consecutive chronic in vivo studies (47 days and longer than 60 days), cardiac output was maintained in excess of 8 l/min. The atrial flow balancing chamber maintained a mean right-to-left pressure gradient of 7.5 and -1.4 mmHg in each respective study. There were no pulmonary complications. Platelet counts, fibrinogen concentrations, and hematocrit values returned to baseline levels within 20 days, whereas bilirubin, serum glutamic-oxaloacetic transaminase, blood urea nitrogen, and creatinine levels returned to normal within 1 week of implant. After the first post-operative day, plasma free hemoglobin levels of less than 10 mg/dl indicated no device-related hemolysis throughout the duration of the studies. At explant (47 day study), pathologic analysis showed no renal infarcts, no tissue necrosis, and no thermal damage. The device was fully encapsulated by 2-4 mm thick fibrous connective tissue. A newly designed textured-to-smooth surface inflow showed no signs of pannus ingrowth or thrombotic complications. These studies demonstrate that this TAH is suitable for long-term implantation.

Animals↗
PubMed2000

Nitrergic and peptidergic innervation in the developing rat heart.

The phenotypic expression and anatomic distribution of nitrergic and peptidergic innervation in the developing rat heart was localized by reduced nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) histochemistry and immunohistochemistry using antibodies against neuronal isoform of nitric oxide synthase (nNOS), neuropeptide Y (NPY) and calcitoningene-related peptide (CGRP). NPY-immunoreactive nerve fibers showed the earliest expression by 16 days of gestation, with preferential innervation of the nodal and perinodal areas, followed by the innervation of the valves and ventricles by postnatal day 7. NPY immunoreactivity was also localized to a large proportion of the intrinsic cardiac ganglia from 16 days of gestation onwards with a progressive increase in the number of neuronal cell bodies per ganglia with age. CGRP-positive nerve fibers appeared by 19 days of gestation and were less dense during the gestational and early postnatal periods, and showed a quantitative increase in density by 7 days, followed by a decrease by 3 weeks postnatal. None of the intrinsic ganglia were stained positive for CGRP, indicating the extrinsic sensory origin of these stained fibers. Nitrergic innervation paralleled the sensory innervation, with the cardiac ganglia and nerve fibers showing a positive labeling from 19 days of gestation onwards. NADPH-d and nNOS were partially co-localized. Double-label immunohistochemistry showed that a considerable proportion of sensory CGRP-immunopositive fibers were also immunoreactive for NOS. The results of the present study show that neuropeptides and nitric oxide are expressed by the late gestational period and that autonomic efferent innervation precedes sensory and nitrergic innervation in the developing heart.

Animals↗
PubMed1991

Immunohistochemical localization of basic and acidic fibroblast growth factors in the developing rat heart.

BACKGROUND: We used biochemical and immunohistochemical techniques to investigate the expression and distribution of immunoreactive basic and acidic fibroblast growth factors (bFGF and aFGF, respectively) in the hearts of rat embryos (11-20 days of gestation) and of postnatal rats (1-35 days after birth). Our purpose was to assess the relation between the cellular distribution of these growth factors and histogenetic and morphogenetic events in the developing heart. METHODS AND RESULTS: Western-blot analysis of heparin-bound material from neonatal heart extracts identified a single band with a molecular weight of approximately 18 kD for both bFGF and aFGF. Five antibodies for bFGF and three for aFGF showed superimposable distribution of immunoreactive bFGF and aFGF in the heart at each stage examined. At the cellular level, these peptides were localized in the cytoplasm and extracellular matrix. In the myocytes, immunostaining was positive throughout the embryonic and neonatal periods. In the majority of the mesenchymal cells of the cushions and endothelial cells of endocardium and vessels, staining was also positive. In the smooth muscle cells of the aorta, other large arteries, and coronary arteries, immunostaining was intensely positive at early stages of development but became faint or negative with increasing cell differentiation. CONCLUSIONS: The wide distribution of immunoreactive bFGF and aFGF that we identified in the developing rat heart suggests that these growth factors play an important role in heart cytodifferentiation and morphogenesis. Their superimposable distribution may reflect functional interaction. The progressive changes in their distribution suggest a changing role for these peptides during organogenesis.

Animals↗