Recurrent abdominal pain.
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Abdominal Pain↗
Biomedical subjects
L Rappaport
Publications and source records attributed to L Rappaport.
Effect of pressure overload on angiotensin receptor expression in the rat heart during early postnatal life.
The development of cardiac hypertrophy during neonatal life and in adults implies different processes. The angiotensin II (Ang II) system is involved in the development of cardiac hypertrophy in adults, but its role in neonates remains unclear. The aim of this study was to estimate the influence of increased hemodynamic load on the developmental pattern of the AT1/AT2 receptor expression in the heart. Two-day-old rats submitted to abdominal aortic constriction (AC) or sham operation were sacrificed 2 h, and 1, 3, and 8 days after surgery. Ang II was evaluated in sera and immunohistology was performed to define the cardiac hypertrophy process. The Ang II receptor subtypes 1 and 2 were quantified at the receptor and mRNA levels by(125)I-Ang II binding and RT-PCR, respectively. Ang II content in sera increased transiently 2 h after surgery in the AC group. In sham-operated, AT1 and AT2 decreased throughout the period studied at both mRNA and receptor levels. However, the AT1 mRNA level decrease was more pronounced than that of AT2 (by 57% and 27%, respectively). AC not only prevented the postnatal decrease in AT mRNA level but resulted in an increase in AT1 mRNA 8 days after surgery (P<0.05). Besides in the AC groups, AT2 mRNA levels but not those of AT1 mRNA were linearly correlated with the left ventricular mass. At the receptor level, a significant transient (1 day after surgery) increase in both AT1 and AT2 was observed. In conclusion, our data demonstrated that imposition of pressure overload soon after birth altered the pattern of AT receptor expression.
Animals↗
Expression of laminin alpha2 chain during normal and pathological growth of myocardium in rat and human.
OBJECTIVES: Fibrosis is a classical feature of cardiac hypertrophy. To date changes within the basal lamina during normal and pathological cardiac growth have been poorly investigated. The goal of the present study was to determine if the expression of the muscle specific subunit of merosin (laminin alpha2 chain) together with that of fibronectin (FN) is modified in the diseased human heart. Laminin alpha2 chain expression was also investigated during physiological and pathological cardiac growth in the rat. METHODS: In ten normal human hearts and ten hearts with idiopathic dilated cardiomyopathy (IDCM), the laminin-alpha2 and FN mRNA levels were quantified by slot-blot using total RNA and the protein distribution was analysed using an immunofluorescence approach. In Wistar rats, laminin alpha2 and FN mRNA expression was analyzed using RNase protection assay (RPA) and slot-blot assays. RESULTS: The amount of laminin alpha2 mRNA did not vary in normal and pathological human hearts whereas it was significantly decreased in renovascular hypertensive rats (-20%) P<0.05 versus normal tissue). The amount of fibronectin mRNA increased in IDMC patients (x2, P<0.05 versus normal tissue), but was unchanged in hypertensive rats. A negative correlation was found between the cardiac laminin-alpha2 level and the age of the patients whatever the cardiac status. During postnatal development in the rat, a similar decrease in cardiac laminin-alpha2 level was observed between 3 and 30 weeks of age. Finally, the immunofluorescent approach failed to detect any alteration in laminin alpha2 distribution within the human myocardium. CONCLUSION: These data indicate that an imbalance between myocyte hypertrophy and the level of laminin-alpha2 might contribute to alterations in sarcolemmal properties, which occur during the development of cardiac hypertrophy and its transition to cardiac failure.
Analysis of Variance↗
Ischemia-reperfusion associated myocardial contractile dysfunction may depend on Ca(2+)-activated cytoskeleton protein degradation.
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Animals↗
Extracellular matrix and growth factors during heart growth.
The effects of growth factors on tissue remodeling and cell differentiation depend on the nature of the extracellular matrix, the type and organization of integrins, the activation of metalloproteinases and the presence of secreted proteins associated to the matrix. These interactions are actually poorly known in the cardiovascular system. We describe here: 1) the main components of extracellular matrix within the cardiovascular system; 2) the role of integrins in the transmission of growth signals; 3) the shift in the expression of the components of the extracellular matrix (fibronectin and collagens) and the stimulation of the synthesis of metalloproteinases during normal and hypertrophic growth of the myocardium; 4) the effects of growth factors, such as Angiotensin II, Fibroblast Growth Factors (FGF), Transforming Growth Factor-beta (TGF-beta), on the synthesis of proteins of the extracellular matrix in the heart.
Animals↗
The extracellular matrix and the cytoskeleton in heart hypertrophy and failure.
Cell characteristics and phenotype depend on the nature of the extracellular matrix, the type and organization of integrins and cytoskeleton. The interactions between these components are poorly known at the myocyte level and during cardiac remodeling associated with cardiac hypertrophy and heart failure. We analyze here the nature and organization of extracellular matrix (ECM) proteins, cytoskeleton and integrins and their regulation by growth factors, such as angiotensin II, in normal myocyte growth and in pathological growth (hypertrophy) of the myocardium and heart failure.
Animals↗
Comparison of the effects of fetal cardiomyocyte and skeletal myoblast transplantation on postinfarction left ventricular function.
OBJECTIVES: Transplantation of fetal cardiomyocytes improves function of infarcted myocardium but raises availability, immunologic, and ethical issues that justify the investigation of alternate cell types, among which skeletal myoblasts are attractive candidates. METHODS: Myocardial infarction was created in rats by means of coronary artery ligation. One week later, the animals were reoperated on and intramyocardially injected with culture growth medium alone (controls, n = 15), fetal cardiomyocytes (5 x 10(6) cells, n = 11), or neonatal skeletal myoblasts (5 x 10(6) cells, n = 16). The injections consisted of a 150-microL volume and were made in the core of the infarct, and the animals were immunosuppressed. Left ventricular function was assessed by echocardiography immediately before transplantation and 1 month thereafter. Myoblast-transplanted hearts were then immunohistologically processed for the expression of skeletal muscle-specific embryonic myosin heavy chain and cardiac-specific connexin 43. RESULTS: The left ventricular ejection fraction markedly increased in the fetal and myoblast groups from 39.3% +/- 3.9% to 45% +/- 3.4% (P =.086) and from 40.4% +/- 3.6% to 47.3% +/- 4.4% (P =.034), respectively, whereas it decreased in untreated animals from 40.6% +/- 4% to 36.7% +/- 2.7%. Transplanted myoblasts could be identified in all animals by the positive staining for skeletal muscle myosin. Conversely, clusters of connexin 43 were not observed on these skeletal muscle cells. CONCLUSIONS: These results support the hypothesis that skeletal myoblasts are as effective as fetal cardiomyocytes for improving postinfarction left ventricular function. The clinical relevance of these findings is based on the possibility for skeletal myoblasts to be harvested from the patient himself.
Animals↗
Thyroid hormones differentially modulate enolase isozymes during rat skeletal and cardiac muscle development.
During muscle development, an isozymic transition of the glycolytic enzyme enolase occurs from the embryonic and ubiquitous alphaalpha-isoform to the muscle-specific betabeta-isoform. Here, we demonstrate a stimulatory role of thyroid hormones on these two enolase genes during rat development in hindlimb muscles and an inhibitory effect on the muscle-specific enolase gene in cardiac muscle. In hindlimb muscles the ubiquitous alpha-transcript level is diminished by hypothyroidism, starting at birth. On the contrary, the more abundant muscle-specific beta-transcript is insensitive to hypothyroidism before establishment of the functional diversification of fibers and is greatly decreased thereafter. Our data support the hypothesis of a role of thyroid hormones in coordinating the expressions of contractile proteins and metabolic enzymes during muscle development. The subcellular localization of isoenolases, established here, is not modified by hypothyroidism. Our results underline the specificity of action of thyroid hormones, which modulate differentially two isozymes in the same muscle and regulate, in opposite directions, the expression of the same gene in two different muscles.
Animals↗
Self-protection by cardiac myocytes against hypoxia and hyperoxia.
Cardiac muscle must maintain a continuous balance between its energy supply and work performed. An important mechanism involved in achievement of this balance is cross talk via chemical signals between cardiac myocytes and the cardiac muscle vascular system. This has been demonstrated by incubating isolated cardiac myocytes in different concentrations of oxygen and then assaying the conditioned media for vasoactive substances on isolated aortic rings and small-resistance arteries. With increasing oxygen concentrations above 6%, cardiac myocytes produce increasing amounts of angiotensin I, which is converted to angiotensin II by the blood vessel. The angiotensin II stimulates vascular endothelial cells to secrete endothelin and increase vascular tone. Below 6% oxygen, cardiac myocytes secrete adenosine, which acts directly on vascular smooth muscle to block the effect of alpha-adrenergic agonists and reduce vascular tone. In an intact heart, the net effect of these 2 regulatory systems would be the maintenance of oxygen concentration within a narrow range at the cardiac myocytes. By acting as oxygen sensors, cardiac myocytes modulate vascular tone according to the needs of the myocytes and reduce potential problems of hypoxia and extensive formation of reactive oxygen species.
Adenosine↗
Infant colic and childhood recurrent abdominal pain syndromes: is there a relationship?
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Abdominal Pain↗
Cellular distribution of Ca2+ pumps and Ca2+ release channels in rat cardiac hypertrophy induced by aortic stenosis.
BACKGROUND: The response of ventricular myocytes to pressure overload is heterogeneous and not spatially coordinated. We investigated whether or not the alterations in SERCA and RyR gene expression are homogeneous within the myocardium. METHODS AND RESULTS: The cellular distribution of mRNAs and proteins encoding the 2 sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) isoforms (SERCA 2a and 2b) and 2 Ca2+ release channels (the ryanodine receptor, RyR, and the IP3 receptor, IP3R) were analyzed by in situ hybridization and immunofluorescence, respectively. Analyses were performed during early (1 and 5 days) and late (1 month) stages of cardiac hypertrophy induced in rat by thoracic aortic stenosis (AS). The results indicated that 1 and 5 days after AS, the cellular distribution of SERCA 2a and RyR2 mRNAs in right ventricle and atrium was similar to controls but the mRNA levels appeared to decrease in some areas of the left ventricle (LV). One month after AS, the distribution of SERCA 2a mRNA and protein became heterogeneous throughout the LV, whereas RyR2 mRNA and protein levels were decreased in a homogeneous manner. SERCA 2b, poorly expressed in both cardiomyocytes and vessels of controls, was increased 4-fold 1 month after AS in coronary arteries only. In both sham (Sh) and AS, SERCA 3 and IP3R mRNAs were mainly found in the vessels. CONCLUSIONS: In severe hypertrophy, decreased accumulation of SERCA 2a was heterogeneous and not compensated by an induction of SERCA 2b in the cardiomyocytes. Decrease in RyR2 expression was more homogeneous and not compensated by an increased IP3R expression.
Animals↗
Can cellular transplantation improve function in doxorubicin-induced heart failure?
BACKGROUND: Transplantation of fetal cardiomyocytes has been shown to improve function of regionally infarcted myocardium, but its effects on global heart failure are still unknown. METHODS AND RESULTS: Heart failure was induced in female mice by intraperitoneal injection of doxorubicin (2 mg/kg twice per week over 2 cycles of 2 weeks separated by a 2-week drug-free period). One week after the end of treatment, left ventricular function was assessed by transthoracic echocardiography (baseline). Animals were then randomized into 3 groups: The treated group (n = 12) received an intramyocardial injection of fetal cardiomyocytes (1 x 10(6) in 10 microL) harvested from transgenic mice expressing the gene of beta-galactosidase, the control group (n = 15) received an equivalent volume of culture medium alone, and 10 sham mice had no surgery. Two weeks and 1 month after transplantation, function was again assessed echocardiographically. At baseline, fractional shortening was not significantly different between the 3 groups. It then significantly increased in cell-treated mice at 2 weeks and 1 month after transplantation (P < 0.002 and P < 0.03 versus baseline, respectively), whereas it did not change in untreated animals. Transplanted cells could not be identified by beta-galactosidase activity or presence of Y chromosome (with 1 exception). CONCLUSIONS: Cellular transplantation can improve function of globally failing hearts by a mechanism that might not necessarily involve the sustained presence of transplanted cells but rather the effects of cardioprotective factors released by them.
Animals↗
Vascular endothelial cell-cardiac myocyte crosstalk in achieving a balance between energy supply and energy use.
In isolated perfused hearts, endothelial cells in the coronary arterial vascular system release substances that can alter the contractility of the cardiac myocytes. There are at least two different substances, one that increases and another that decreases the contractility of cardiac myocytes. The rate of release of these endothelial-derived cardioactive substances depends on the oxygen tension in the immediate vicinity of the cardiac myocytes. As the local oxygen tension increases the contractility changes in the same direction. The oxygen sensor in this regulatory system is the cardiac myocyte, which then releases substances that regulate the secretion of endothelin and a relaxant by endothelial cells. The result is a loop involving cross talk between coronary endothelial cells and cardiac myocytes to modulate cardiac contractility in accordance with the oxygen supply to the cardiac myocytes. Preliminary data suggest that the change in contractility is related to a change in structure and position of the cross bridge due to phosphorylation of a protein in the thick filament.
Animals↗
Microvasculature in angiotensin II-dependent cardiac hypertrophy in the rat.
The long-lasting effect of angiotensin II (Ang II) on the microvasculature in the rat left ventricle was studied. Immunolabeling of ventricular cryosections combined with morphometric analysis allowed us to (1) distinguish between capillaries and arterioles and (2) precisely evaluate their respective densities in the endomyocardium. Ang II-induced hypertensive cardiac hypertrophy was associated with an 18% decrease in capillary density (P<0.05) and an increase in arteriole density (+54%, P<0.001). Treatments with losartan or PD123319, the respective antagonists of the angiotensin subtype 1 and subtype 2 receptors, prevented the increase in arteriolar density, whereas only losartan, which restored normal arterial pressure, prevented changes in capillary density. Taken together, these results indicate that Ang II-induced cardiac hypertrophy was associated with capillary rarefaction and arteriolar growth, the 2 processes being independently regulated.
Angiotensin II↗
Cytoskeleton and mitochondrial morphology and function.
It has been well established that the cytoskeleton is an essential modulator of cell morphology and motility, intracytoplasmic transport and mitosis, however cytoskeletal linkage to the organelles has not been unequivocally demonstrated. Indeed, cytoskeleton appears to be essential in determining and modulating gene phenotype as a function of cellular environment. According to recent studies, the organization of the cytoskeleton network together with associated protein(s) could be essential in regulating mitochondrial function and particularly the permeability of the mitochondrial outer membrane to ADP. The aim of this chapter is to summarize the main properties of the cytoskeletal environment of mitochondria and the possible role(s) of this network in mitochondrial function in myocytes.
Adenosine Diphosphate↗
[Cellular cardiomyoplasty: state of the art, evaluation, and future possibilities].
Cellular cardiomyoplasty, or the transplantation of myogenic cells into the myocardial tissues, could emerge as a therapeutic alternative in patients with cardiac failure. It depends on several procedures: implantation of cell types, syngenic embryonic cardiomycocytes, allogenic and autogenic cardiac muscle cells. These cells carne into contact with host cardiomyocytes and could contract in a synchronous fashion. Experimental data suggests that this technique could improve global left ventricular function in the post-infarction period or in dilated cardiomyopathy even though the precise mechanism of this improvement is not fully understood. Many difficulties remain, the cell types have an oncogenic potential; syngenic foetal cells are weakly immunogenic but their use is limited by ethical and problems of supply. Therefore, auto-transplantation either of cardiomycocytes obtained by endomyocardial biopsy or of adult skeletal muscle, could be a potential clinical option.
Adult↗
Study of regulation of mitochondrial respiration in vivo. An analysis of influence of ADP diffusion and possible role of cytoskeleton.
The purpose of this work was to investigate the mechanism of regulation of mitochondrial respiration in vivo in different muscles of normal rat and mice, and in transgenic mice deficient in desmin. Skinned fiber technique was used to study the mitochondrial respiration in the cells in vivo in the heart, soleus and white gastrocnemius skeletal muscles of these animals. Also, cardiomyocytes were isolated from the normal rat heart, permeabilized by saponin and the "ghost" (phantom) cardiomyocytes were produced by extraction of myosin with 800 mM KCl. Use of confocal immunofluorescent microscopy and anti-desmin antibodies showed good preservation of mitochondria and cytoskeletal system in these phantom cells. Kinetics of respiration regulation by ADP was also studied in these cells in detail before and after binding of anti-desmine antibodies with intermediate filaments. In skinned cardiac or soleus skeletal muscle fibers but not in fibers from fast twitch skeletal muscle the kinetics of mitochondrial respiration regulation by ADP was characterized by very high apparent Km (low affinity) equal to 300-400 microM, exceeding that for isolated mitochondria by factor of 25. In skinned fibers from m. soleus, partial inhibition of respiration by NaN3 did not decrease the apparent Km for ADP significantly, this excluding the possible explanation of low apparent affinity of mitochondria to ADP in these cells by its rapid consumption due to high oxidative activity and by intracellular diffusion problems. However, short treatment of fibers with trypsin decreased this constant value to 40-70 microM, confirming the earlier proposition that mitochondrial sensitivity to ADP in vivo is controlled by some cytoplasmic protein. Phantom cardiomyocytes which contain mostly mitochondria and cytoskeleton and retain the normal shape, showed also high apparent Km values for ADP. Therefore, they are probably the most suitable system for studies of cellular factors which control mitochondrial function in the cells in vivo. In these phantom cells anti-desmin antibodies did not change the kinetics of respiration regulation by ADP. However, in skinned fibers from the heart and m. soleus of transgenic desmin-deficient mice some changes in kinetics of respiration regulation by ADP were observed: in these fibers two populations of mitochondria were observed, one with usually high apparent Km for ADP and the second one with very low apparent Km for ADP. Morphological observations by electron microscopy confirmed the existence of two distinct cellular populations in the muscle cells of desmin-deficient mice. The results conform to the conclusion that the reason for observed high apparent Km for ADP in regulation of oxidative phosphorylation in heart and slow twitch skeletal muscle cells in vivo is low permeability of mitochondrial outer membrane porins but not diffusion problems of ADP into and inside the cells. Most probably, in these cells there is a protein associated with cytoskeleton, which controls the permeability of the outer mitochondrial porin pores (VDAC) for ADP. Desmin itself does not display this type of control of mitochondrial porin pores, but its absence results in appearance of cells with disorganised structure and of altered mitochondrial population probably lacking this unknown VDAC controlling protein. Thus, there may be functional connection between mitochondria, cellular structural organisation and cytoskeleton in the cells in vivo due to the existence of still unidentified protein factor(s).
Adenosine Diphosphate↗
Does transplantation of cardiomyocytes improve function of infarcted myocardium?
BACKGROUND: The feasibility of successfully grafting fetal cardiomyocytes into infarcted myocardium is now established, but the functional effects of such a procedure still remain elusive. METHODS AND RESULTS: Twenty-three female rats underwent 45 minutes of coronary artery occlusion followed by 30 minutes of reperfusion. At this time point, 13 animals received intramyocardial injections of fetal cardiomyocytes (6 x 10(6) cells in 60 microL of culture medium) in the once ischemic area, whereas the 10 control rats were injected with an equivalent volume of culture medium alone. One month after transplantation, left ventricular function was assessed by two-dimensional (2D) and Doppler echocardiography using a short focus 10- to 13-MHz transducer, and a numeric acquisition of 2D images up to 65.5 frames/second. Explanted hearts were then processed for histological assessment of infarct size. The presence of male donor cells into female recipient myocardium was detected by fluorescent in situ hybridization using a deoxyribonucleic acid probe specific for Y chromosome. Cellular transplantation resulted in an improved left ventricular function, as demonstrated by significantly higher 2D ejection fraction and cardiac output (P<.02 and P<.02 versus control hearts, respectively). The histological sections of female recipient myocardium were Y-positive in all but one heart, thereby suggesting that this improvement of function was causally related to the presence of transplanted cells. CONCLUSIONS: These data suggest that transplantation of cardiomyocytes might be an effective means of improving function of infarcted myocardium.
Animals↗