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1.
Thyroid ; 16(10): 1025-31, 2006 Oct.
Article in English | MEDLINE | ID: mdl-17042689

ABSTRACT

Radioiodine (I-131) therapy is of proven efficacy for differentiated thyroid carcinoma. However, its efficacy relies on specific uptake mechanisms, which may be lost during the evolution of the disease. Attempts to increase the iodine uptake of such tumors have been made using retinoic acid because it exerts redifferentiating effects on thyrocytes. This study aims to assess the capability of the retinoic acid (RA) treatment to reinforce iodine 131-irradiation efficacy for metastatic and progressive multi-irradiated thyroid cancer. In this clinical prospective study, 11 patients (mean age +/- 1 SD = 61 +/- 12 years, sex ratio M/F = 5/6) with a progressive disease despite iterative surgery and iodine irradiations were treated with 13-cis-retinoic acid (1.5 mg/kg day) over 8 weeks prior to I-131 irradiation. The redifferentiating effect of RA was evaluated by serum thyroglobulin (Tg) monitoring during RA treatment and qualitative analysis of iodine uptake on the post-therapeutic whole body scan. The clinical usefulness of RA treatment was assessed by clinical follow-up, Tg monitoring, and tumor size. No serious event that could possibly be related to the treatment was reported. The mean follow up time was 24.2 +/- 12 months (range 3-46 months). Iodine uptake was only slightly improved in two patients. Nevertheless, the clinical benefits of RA seem to be very poor. Five patients died of a metastatic disease. Five others presented new clinical evidences of a progressive disease. In conclusion, this prospective study demonstrates the absence of efficacy of I-131 irradiation combined with RA for the treatment of patients with aggressive, rapidly growing metastatic thyroid cancer. Thus, patients with highly aggressive disease, rapidly growing in a short period from 2 to 6 months, should not be considered for RA therapy.


Subject(s)
Neoplasm Metastasis/drug therapy , Thyroid Neoplasms/drug therapy , Thyroid Neoplasms/radiotherapy , Tretinoin/therapeutic use , Adult , Aged , Combined Modality Therapy , Female , Humans , Iodine Radioisotopes/therapeutic use , Male , Middle Aged , Neoplasm Metastasis/pathology , Neoplasm Metastasis/radiotherapy , Neoplasm Staging , Prospective Studies , Reproducibility of Results , Thyroid Neoplasms/pathology , Thyroid Neoplasms/surgery
2.
Genes Chromosomes Cancer ; 32(4): 390-1, 2001 Dec.
Article in English | MEDLINE | ID: mdl-11746981

ABSTRACT

The RET proto-oncogene is responsible for inherited medullary thyroid cancer syndromes. RET is also found mutated in sporadic medullary thyroid cancer (MTC) and rearranged in sporadic papillary thyroid carcinomas. Here, we describe a previously unreported germline RET mutation at codon 603 in exon 10 associated with both MTC and nonmedullary thyroid cancer (NMTC) in a kindred. RET may thus not be excluded as a potential candidate for predisposition to some forms of NMTC.


Subject(s)
Carcinoma, Papillary/genetics , Drosophila Proteins , Germ-Line Mutation/genetics , Proto-Oncogene Proteins/genetics , Receptor Protein-Tyrosine Kinases/genetics , Thyroid Neoplasms/genetics , Adult , Amino Acid Substitution/genetics , Female , Genetic Linkage/genetics , Genetic Predisposition to Disease/genetics , Humans , Male , Pedigree , Proto-Oncogene Mas , Proto-Oncogene Proteins c-ret
3.
Eur J Endocrinol ; 144(1): 37-44, 2001 Jan.
Article in English | MEDLINE | ID: mdl-11174835

ABSTRACT

OBJECTIVE: The aim of this prospective study is to update our knowledge of the chronology of pheochromocytoma occurrence in multiple endocrine neoplasia type 2 (MEN 2), and to better manage MEN 2 patients after the genetic diagnosis. DESIGN: Eighty-seven non-index gene carrier MEN 2 patients were included in this prospective study: 84 patients with MEN 2A (from 52 families) and 3 with MEN 2B (from 3 families). METHODS: Medullary thyroid carcinoma (MTC) was diagnosed by measuring plasma calcitonin in basal conditions or after pentagastrin stimulation. The search for pheochromocytoma consisted of clinical evaluation, 24 h determination of urinary catecholamines and adrenal imaging. The mean age at genetic diagnosis of MEN 2 was 14.0+/-7.0 years, the mean duration for the follow-up was 7.6+/-2.8 years. RESULTS: All 87 patients had a MTC detected at the same time as the genetic diagnosis was made. Urinary catecholamine measurements led to the diagnosis of pheochromocytoma and a combination of imaging techniques enabled the correct localization of both unilateral or bilateral adrenal involvement. Pheochromocytoma was detected simultaneously with MTC in only seven patients, and seven others were detected throughout the follow-up. Of the 14 patients with pheochromocytoma, 11 had bilateral involvement: nine were initially bilateral and two became so during follow-up. CONCLUSION: This study demonstrates that in MEN 2, MTC is the lesion which appears earliest. Pheochromocytoma develops later during the evolution of the disease, and necessitates regular clinical and biological monitoring throughout follow-up. Determination of urinary and/or plasma catecholamines and metanephrines should be performed to detect pheochromocytoma. Imaging techniques lead to the detection of both unilateral and bilateral pheochromocytoma, thus making video-assisted laparoscopic adrenalectomy possible.


Subject(s)
Adrenal Gland Neoplasms/genetics , Drosophila Proteins , Multiple Endocrine Neoplasia Type 2a/genetics , Pheochromocytoma/genetics , Adolescent , Adrenal Gland Neoplasms/diagnosis , Adrenal Gland Neoplasms/surgery , Adult , Calcitonin/blood , Carcinoma, Medullary/diagnosis , Catecholamines/blood , Catecholamines/urine , Child , Child, Preschool , Humans , Infant , Magnetic Resonance Imaging , Metanephrine/blood , Metanephrine/urine , Multiple Endocrine Neoplasia Type 2b/genetics , Mutation , Pentagastrin , Pheochromocytoma/diagnosis , Pheochromocytoma/surgery , Prospective Studies , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins c-ret , Receptor Protein-Tyrosine Kinases/genetics , Thyroid Neoplasms/diagnosis , Tomography, X-Ray Computed
4.
Therapie ; 51(5): 550-3, 1996.
Article in French | MEDLINE | ID: mdl-9138391

ABSTRACT

In France, radiopharmaceuticals have been considered as drugs since 1992. Few adverse reactions with radiopharmaceuticals were described in the literature. Some authors have reported a rate of 1 to 6 reactions per 100,000 injections. The purpose of the present study was to evaluate the prevalence of radiopharmaceutical-induced side effects. A prospective survey was performed from November 1993 to May 1995 (during 18 months) in the Department of Nuclear Medicine of the University Hospital in Toulouse. There were 14,794 injections of radiopharmaceuticals (99mTc-phytate, 99mTc-microspheres of serum albumin, 99mTc-dimercapto-succinic acid (DMSA), 99mTc-hydroxymethyldiphosphonate (HMDP), 99Tc-colloid, 99mTc, 99mTc-sestamibi, Thallium-201). Three side effects were reported: one case of necrosis at the injection site, one case of vomiting and one case of dizziness. All the cases occurred with Tc99m-pyrophosphate. According to the WHO definition, the first side effect was classified as 'serious'. The causal relationship was unlikely for the first and second case and probable for the third. The outcome of these side effects was always favorable.


Subject(s)
Radiopharmaceuticals/adverse effects , Adult , Aged , Female , France , Health Surveys , Humans , Male , Middle Aged , Product Surveillance, Postmarketing , Prospective Studies
5.
Circ Res ; 70(5): 999-1005, 1992 May.
Article in English | MEDLINE | ID: mdl-1568307

ABSTRACT

Sarcomeric actin genes, alpha-cardiac and alpha-skeletal, are coexpressed in neonatal rodent hearts and are regulated in response to hormonal and hemodynamic stimuli; however, their precise developmental pattern of expression has not been determined, and it is unknown whether they are coexpressed during senescence. We have, therefore, investigated the accumulation of sarcomeric actin transcripts in rat heart during fetal and postnatal development and with senescence by two different techniques: primer extension analysis with an oligonucleotide common to both sarcomeric actins and RNA hybridization with specific cardiac alpha-actin cRNA probes. We found that at 17-19 days in utero both isogenes are coexpressed and alpha-skeletal actin mRNAs represent 28.0 +/- 0.8% of the sarcomeric actin mRNA total. Skeletal actin mRNAs increase to 40% of the total 1 week after birth (NS, p = 0.15), remain constant for 3 weeks, and decrease to less than 20% of the total in ventricles and atria of 1-month-old rats. The alpha-skeletal actin transcripts further decline to less than 5% of the total at 2 months of age and do not reaccumulate in senescent animals. There was no significant difference between male and female rat ventricles. By comparison with the known accumulations of alpha- and beta-myosin heavy chain mRNAs, our results demonstrate that whatever the developmental stage the kinetics of expression for the sarcomeric myosin and actin multigene families are independent.


Subject(s)
Actins/genetics , Aging , Gene Expression , Heart/growth & development , Myocardium/chemistry , Sarcomeres/chemistry , Age Factors , Animals , Female , Male , RNA Probes , RNA, Messenger , Rats , Rats, Inbred Strains , Sex Factors
6.
Am J Physiol ; 262(3 Pt 2): R364-9, 1992 Mar.
Article in English | MEDLINE | ID: mdl-1532697

ABSTRACT

In the mammalian heart, the expression of genes encoding proteins responsible for contraction, relaxation, and endocrine function changes in hypertrophy resulting from hemodynamic overload. Different mechanisms are involved in this mechanogenic transduction, including 1) differential expression of myosin and actin multigene families, which may account for the decreased velocity of contractile element shortening in hypertrophied heart, 2) nonactivation of the sarcoplasmic reticulum Ca(2+)-ATPase gene, which may explain the increased duration of isometric relaxation, and finally 3) activation in the ventricle of the atrial natriuretic factor gene that is responsible in part for the high plasma levels of this peptide. It is increasingly apparent that these changes are independently regulated, but little is known about the mechanisms underlying this regulation. Preliminary results indicate that it is now possible to analyze the early time course or transcription for each gene after the imposition of hemodynamic overload. This should significantly enhance our understanding of the regulatory mechanisms involved in the phenoconversions of the hemodynamically overloaded heart.


Subject(s)
Actins/genetics , Gene Expression Regulation , Heart/physiology , Muscles/physiology , Myosins/genetics , Animals , Cardiomegaly/physiopathology , Gene Expression , Heart/physiopathology , Humans , Multigene Family , RNA, Messenger/genetics , RNA, Messenger/metabolism , Stress, Mechanical
7.
Am J Physiol ; 261(4 Suppl): 23-6, 1991 10.
Article in English | MEDLINE | ID: mdl-1833991

ABSTRACT

The properties of the calcium pump system of sarcoplasmic reticulum (SR) were studied in a series of 34 rats subjected to cardiac overload and 19 sham-operated animals. Total homogenates of left ventricle were analyzed by measuring the oxalate-supported Ca2+ uptake rate, the steady-state level of the phosphorylated intermediate of Ca(2+)-adenosine triphosphatase (Ca(2+)-ATPase) (EP), and the amount of Ca(2+)-ATPase mRNA. All three parameters decreased gradually as a function of the relative left ventricular weight increase. The calcium-sensitivity curves showed that the velocity of Ca2+ transport in SR from the hypertrophied heart is diminished at low as well as optimal Ca2+ concentrations, with the dissociation constant (Kd) value for Ca2+ unchanged from that of the control preparation. Taken together with the results presented in our recent publication (De la Bastie, Levitsky, Mercadier, Marotte, Wisnewsky, Brovkovivh, Schwartz, and Lompré, Circ. Res. 66: 554-564, 1990), these data strongly indicate that differences in the Ca2+ pump activities of SR from normal and hypertrophied rat hearts are due to quantitative rather than qualitative changes of the Ca(2+)-ATPase protein.


Subject(s)
Calcium-Transporting ATPases/metabolism , Cardiomegaly/physiopathology , Sarcoplasmic Reticulum/physiology , Animals , Biological Transport , Calcium/metabolism , Calcium-Transporting ATPases/genetics , Cardiomegaly/enzymology , Gene Expression , Male , Myocardium/metabolism , Phosphorylation , RNA, Messenger/analysis , Rats , Rats, Inbred Strains , Reference Values , Sarcoplasmic Reticulum/chemistry , Sarcoplasmic Reticulum/enzymology
8.
J Clin Invest ; 88(1): 323-30, 1991 Jul.
Article in English | MEDLINE | ID: mdl-2056125

ABSTRACT

Expression of the two sarcomeric actins, alpha-skeletal and alpha-cardiac, is regulated in the rodent heart in response to developmental, hormonal, and hemodynamic stimuli. Little is known in man, except that both isogenes were found to be coexpressed in three adult ventricles. In this report, we investigated the isoactin mRNA composition in ventricles from 21 control patients (4 fetal, 5 juvenile, 12 adult) and from 15 patients undergoing cardiac transplantation (5 idiopathic dilated cardiomyopathies, 5 ischemic myopathies with myocardial infarcts, 5 diverse etiologies) by two different and complementary techniques: RNA dot blot analysis with specific cDNA probes, and primer extensions with an oligonucleotide common to alpha-cardiac and alpha-skeletal actins. In the case of dot blot analysis, quantification of each isoform was performed by using as standards RNA transcripts obtained from cloned human alpha-actin sequences, and the total amount of sarcomeric actin mRNA was evaluated as a function of total poly(A+)RNA. We found that both isogenes are always coexpressed, and that the isoactin pattern changes during development. In utero and in neonatal hearts, alpha-skeletal actin mRNA represents less than or equal to 20% of sarcomeric actins, it increases to 48 +/- 6% during the first decade after birth and becomes the predominant isoform of adult hearts (60.4 +/- 8.5%). The 15 adult failing hearts exhibited the same isoactin pattern as the control ones (62.84 +/- 11.06%), and there was no difference in expression between patients with dilated cardiomyopathy or ischemic heart disease. These observations demonstrate that cardiac development in man, in contrast to rodent heart, is characterized by an up-regulation of the skeletal actin gene, the expression of which does not change in hypertrophied and failing hearts, and suggest that the actin and myosin heavy chain families are independently regulated in human heart.


Subject(s)
Actins/genetics , Fetal Heart/metabolism , Heart Failure/metabolism , Muscles/metabolism , Myocardium/metabolism , RNA, Messenger/analysis , Adolescent , Adult , Age Factors , Child , Child, Preschool , Female , Gene Expression Regulation , Humans , Infant , Male , Middle Aged , Pregnancy
9.
Mol Cell Biochem ; 104(1-2): 101-7, 1991.
Article in English | MEDLINE | ID: mdl-1833621

ABSTRACT

The cardiac ventricular myosin heavy chain phenotype is developmentally and hormonally regulated, but less is known concerning the actin phenotype. In this study, the levels of accumulation of alpha-skeletal and alpha-cardiac actin mRNAs were investigated in rat and human ventricles by primer extension assays. In rat, the two iso-mRNAs are present in approximately equal amounts from birth until 15 days of age and the cardiac form is predominant in adult and senescent hearts. Hypothyroid development has no effect, at least during the first two weeks of age. In man, the two isoactins are co-expressed to similar ratios in one control heart and in one failing heart. It therefore appears that myosin heavy chain and actin multigene families are both expressed in a species specific fashion but are independently regulated within a species. Preliminary results from nuclear run-on assays are presented that indicate differences in the level of transcription of the alpha-actin and beta-myosin heavy chain isogenes in the rat heart.


Subject(s)
Actins/genetics , Gene Expression Regulation , Heart/growth & development , Myosins/genetics , Actins/metabolism , Animals , Cardiomegaly/metabolism , Female , Heart Arrest/metabolism , Humans , Male , Multigene Family , Myocardial Contraction , Myosins/metabolism , RNA, Messenger/metabolism , Rats
10.
Circ Res ; 66(2): 554-64, 1990 Feb.
Article in English | MEDLINE | ID: mdl-2137041

ABSTRACT

The reduction in Ca2+ concentration during diastole and relaxation occurs differently in normal hearts and in hypertrophied hearts secondary to pressure overload. We have studied some possible molecular mechanisms underlying these differences by examining the function of the sarcoplasmic reticulum and the expression of the gene encoding its Ca2(+)-ATPase in rat hearts with mild and severe compensatory hypertrophy induced by abdominal aortic constriction. Twelve sham-operated rats and 31 operated rats were studied 1 month after surgery. Eighteen animals exhibited mild hypertrophy (left ventricular wt/body wt less than 2.6) and 13 animals severe hypertrophy (left ventricular wt/body wt greater than 2.6). During hypertrophy we observed a decline in the function of the sarcoplasmic reticulum as assessed by the oxalate-stimulated Ca2+ uptake of homogenates of the left ventricle. Values decreased from 12.1 +/- 1.2 nmol Ca2+/mg protein/min in sham-operated rats to 9.1 +/- 1.5 and 6.7 +/- 1.1 in rats with mild and severe hypertrophy, respectively (p less than 0.001 and p less than 0.001, respectively, vs. shams). This decrease was accompanied by a parallel reduction in the number of functionally active CA2(+)-ATPase molecules, as determined by the level of Ca2(+)-dependent phosphorylated intermediate: 58.8 +/- 7.4 and 48.1 +/- 13.5 pmol P/mg protein in mild and severe hypertrophy, respectively, compared with 69.7 +/- 8.2 in shams (p less than 0.05 and p less than 0.01, respectively, vs. shams). Using S1 nuclease mapping, we observed that the Ca2(+)-ATPase messenger RNA (mRNA) from sham-operated and hypertrophied hearts was identical. Finally, the relative level of expression of the Ca2(+)-ATPase gene was studied by dot blot analysis at both the mRNA and protein levels using complementary DNA clones and a monoclonal antibody specific to the sarcoplasmic reticulum Ca2(+)-ATPase. In mild hypertrophy, the concentrations of Ca2(+)-ATPase mRNA and protein in the left ventricle were unchanged when compared with shams (mRNA, 93.8 +/- 10.6% vs. sham, NS; protein, 105.5 +/- 14% vs. sham, NS). in severe hypertrophy, the concentration of Ca2(+)-ATPase mRNA decreased to 68.7 +/- 12.9% and that of protein to 80.1 +/- 15.5% (p less than 0.001 and p less than 0.05, respectively), whereas the total amount of mRNA and enzyme per left ventricle was either unchanged or slightly increased. The slow velocity of relaxation of severely hypertrophied heart can be at least partially explained by the absence of an increase in the expression of the Ca2(+)-ATPase gene and by the relative diminution in the density of the Ca2+ pumps.(ABSTRACT TRUNCATED AT 400 WORDS)


Subject(s)
Calcium-Transporting ATPases/genetics , Cardiomegaly/physiopathology , Gene Expression Regulation, Enzymologic , Hypertension/complications , Sarcoplasmic Reticulum/physiology , Animals , Calcium/metabolism , Calcium-Transporting ATPases/metabolism , Cardiomegaly/etiology , Cardiomegaly/genetics , Male , Phosphorylation , RNA, Messenger/metabolism , Rats , Rats, Inbred Strains , Sarcoplasmic Reticulum/enzymology
11.
Am J Physiol ; 257(3 Pt 2): H979-87, 1989 Sep.
Article in English | MEDLINE | ID: mdl-2528919

ABSTRACT

Activation of atrial natriuretic factor (ANF) gene expression has been reported in the rat ventricle in several models of hemodynamic overload, including hypertension. However, nothing is known about the potential trigger(s) and the time course of this activation during the development of hypertension. We measured aortic blood pressure, left ventricular hypertrophy (LVH), and left ventricular ANF mRNA concentration (LV ANF mRNA) in a first group of rats (study A) killed at 5 and 18 h and 2, 4, 6, 9, 15, and 30 days after suprarenal coarctation of the abdominal aorta. Coarctation induced a progressive rise in aortic blood pressure and left ventricular mass. We observed a biphasic accumulation of ANF mRNA in the left ventricle with a peak at day 4 averaging 20 times the control value long before stable hypertension and hypertrophy were achieved, followed by a decrease until day 9. This decrease was followed by a new rise, which stabilized around 10 times the control value seen during stable hypertension and hypertrophy. In a second group of rats killed at days 4 and 30 (study B), we determined, in addition to the previous parameters, left ventricular end-diastolic pressure (LVEDP), plasma renin (PRC), and plasma ANF concentrations. LVEDP and PRC were markedly increased at day 4, but at day 30, during stable hypertension and hypertrophy, these parameters returned to control values, whereas plasma ANF was increased. Using immunocytochemistry, we looked in a third group of rats (study C) for the presence of the immunoreactive peptide at days 4 and 30.(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Atrial Natriuretic Factor/genetics , Gene Expression Regulation , Heart/physiopathology , Hypertension/genetics , Animals , Aorta/physiopathology , Aortic Coarctation/complications , Aortic Coarctation/genetics , Aortic Coarctation/metabolism , Atrial Natriuretic Factor/blood , Atrial Natriuretic Factor/metabolism , Blood Pressure , Cardiomegaly/etiology , Cardiomegaly/metabolism , Heart Ventricles , Immunohistochemistry , Male , Myocardium/metabolism , RNA, Messenger/metabolism , Rats , Renin/blood , Time Factors
12.
FEBS Lett ; 249(1): 35-41, 1989 May 22.
Article in English | MEDLINE | ID: mdl-2542094

ABSTRACT

Sarcoplasmic reticulum Ca2+-ATPase cDNA clones have been isolated from an adult rat heart cDNA library and the nucleotide sequence of the Ca2+-ATPase mRNA determined. The sequence has an open reading frame of 997 codons. It is identical to a cDNA isolated from a rat stomach cDNA library and 90% isologous to the rabbit and human slow/cardiac cDNAs. Nuclease S1 mapping analysis indicates that this sequence corresponds to the main Ca2+-ATPase mRNA present in heart and in slow skeletal muscle and that it is expressed in various proportions in smooth and non-muscle tissues, together with another isoform which differs from the cardiac form in the sequence of its 3'-end.


Subject(s)
Calcium-Transporting ATPases/genetics , Myocardium/enzymology , RNA, Messenger/isolation & purification , Sarcoplasmic Reticulum/enzymology , Amino Acid Sequence , Animals , Base Sequence , Calcium-Transporting ATPases/isolation & purification , Cloning, Molecular , DNA/isolation & purification , Endonucleases , Male , Molecular Sequence Data , Muscle, Smooth/enzymology , Rats , Rats, Inbred Strains , Single-Strand Specific DNA and RNA Endonucleases , Stomach/enzymology
13.
J Biol Chem ; 263(27): 13922-9, 1988 Sep 25.
Article in English | MEDLINE | ID: mdl-2458355

ABSTRACT

The Ca2+ pumps associated with human platelet plasma and intracellular membranes have been further characterized by their sensitivity to trypsin. (a) Tryptic degradation of the Ca2+-ATPases has been followed by immunoblotting. It resulted in fragmentation into peptides of 80, 55, 35, and 24 kDa for both enzymes. Subcomplete hydrolysis obtained with a ratio of trypsin/membrane protein of 0.05-0.1 for the two Ca2+ pumps resulted in the total disappearance of the 100-, 80-, and 35-kDa fragments. However, maximum degradation was reached within 1 min for the intracellular enzyme but needed 5 min of incubation for the plasma membrane enzyme. (b) This effect of trypsin has been correlated with its effect on both the Ca2+-ATPase activities. The plasma membrane enzyme showed a maximum inhibition of 50-60% which was obtained using a trypsin/protein ratio of 0.1 and 5 min of incubation. A much higher trypsin sensitivity was observed for the intracellular enzyme because the maximum inhibition reached 80% after only 1 min of incubation. (c) Finally, the two Ca2+ transport systems studied showed different trypsin reactivities; the Ca2+ uptake by the plasma membrane vesicles was inhibited by 20-25%, and this maximum inhibition was observed after 5 min of incubation with trypsin. In contrast, the Ca2+ transport associated with the intracellular membrane vesicles was difficult to detect after trypsin treatment. Taken together, the results show that the two Ca2+ pumps can be distinguished by their trypsin sensitivity.


Subject(s)
Blood Platelets/enzymology , Calcium-Transporting ATPases/blood , Calcium/blood , Ion Channels/metabolism , Trypsin/metabolism , Animals , Biological Transport , Cell Membrane/enzymology , Electrophoresis, Polyacrylamide Gel , Humans , Immunoassay , Intracellular Membranes/enzymology , Kinetics , Muscles/enzymology , Peptide Fragments/metabolism , Rabbits , Sarcoplasmic Reticulum/enzymology
14.
FEBS Lett ; 229(1): 45-8, 1988 Feb 29.
Article in English | MEDLINE | ID: mdl-2831089

ABSTRACT

We have investigated some characteristics of the sarcoplasmic reticulum (Ca2+ + Mg2+)-dependent ATPase (Ca2+-ATPase) mRNA from smooth muscle using specific cDNA probes isolated from a rat heart cDNA library. RNA blot analysis has shown that the Ca2+-ATPase mRNA expressed in smooth muscle is identical in size to the cardiac mRNA but differs from that of fast skeletal muscle. S1 nuclease mapping has moreover shown that the cardiac and smooth muscle isoforms possess different 3'-end sequences. These results indicate that a distinct sarcoplasmic reticulum Ca2+-ATPase mRNA is present in smooth muscle.


Subject(s)
Ca(2+) Mg(2+)-ATPase/genetics , Calcium-Transporting ATPases/genetics , Isoenzymes/genetics , Muscle, Smooth/enzymology , Muscles/enzymology , Myocardium/enzymology , RNA, Messenger/analysis , Sarcoplasmic Reticulum/enzymology , Animals , DNA/analysis , Electrophoresis, Polyacrylamide Gel , Endonucleases/metabolism , Muscle, Smooth/ultrastructure , Rats , Single-Strand Specific DNA and RNA Endonucleases
15.
Eur J Clin Invest ; 17(3): 194-201, 1987 Jun.
Article in English | MEDLINE | ID: mdl-2441994

ABSTRACT

Cardiac overload was studied in rats by abdominal aortic constriction, which increased the left ventricular weight by 59% after 12 days. During the transition, which precedes the compensatory hypertrophy, both total RNA and poly(A)-containing messenger RNA increased. The concentration of these polynucleotides peaked by day 4 after constriction, rising from 1.27 +/- 0.3 to 1.88 +/- 0.2 mg g-1 fresh weight for total RNA, and from 38 +/- 24 to 62 +/- 12 micrograms g-1 fresh weight for poly(A)-containing RNA, and returned to normal by day 12. However, the total amount per ventricle of both RNAs remained high. Poly(A)-containing RNA prepared from normal heart was hybridized to its cDNA copy. These results were expressed as the percentage of hybridization vs. the log 10 of the product of the poly(A)-containing RNA concentration and the time (Rot), and in computer analysis were described by division into three different frequency components. In normal hearts, the Rot 1/2 values of these components were, respectively, 3.98 X 10(-3), 0.338 and 21.380 mol.s.1(-1), which correspond to 2-3, 240 and 12,200 different sequences that were copied 22,000-33,000, 310 and 5 times, respectively. Four and 30 days after banding there was a harmonious enhancement of the number of the copies without any change in the number of different sequences, and the three different hybridization curves were superimposed. In conclusion, cardiac overload raises the poly(A)-containing RNA concentration, probably by stimulating transcription, but no major changes occur in any of the frequency classes.


Subject(s)
Cardiomegaly/metabolism , Myocardium/metabolism , Poly A/metabolism , RNA, Messenger/metabolism , RNA/metabolism , Animals , Aorta, Abdominal/physiology , Cardiomegaly/etiology , Constriction , DNA/genetics , Kinetics , Liver/metabolism , Male , Muscles/metabolism , Nucleic Acid Hybridization , Poly A/genetics , RNA, Messenger/genetics , Rats , Rats, Inbred Strains
16.
J Am Coll Cardiol ; 9(5): 1024-30, 1987 May.
Article in English | MEDLINE | ID: mdl-3106447

ABSTRACT

The cardiac myosin phenotype, an important determinant of myocardial contractility, is modified by chronic increases in hemodynamic load. To quantify the proportion of atrial alpha-myosin heavy chain in various types of left atrial overload and to assess the possible relation between this proportion and atrial size, 34 patients were studied, 4 with Wolff-Parkinson-White syndrome, 29 with various types of mitral valve dysfunction and 1 with an atrial septal defect. Four normal autopsy hearts were also studied. The proportion of alpha-myosin heavy chain among total (alpha plus beta) myosin heavy chains was determined in each atrial sample, using an enzyme-linked immunosorbent assay. The size of the left atrium was assessed by one- and two-dimensional echocardiography. Alpha-myosin heavy chain was the main isoform present in the normal atria (85.5 +/- 9% of total myosin heavy chains). Patients with pure tight mitral stenosis (n = 9), mitral stenosis plus mild regurgitation (n = 8) and severe mitral regurgitation (n = 8), who had a higher indexed left atrial transverse diameter than those with Wolff-Parkinson-White syndrome (33 +/- 6, 39 +/- 10 and 46 +/- 5 versus 19.5 +/- 2 mm/m2, p less than 0.01, p less than 0.001 and p less than 0.001, respectively), also demonstrated a much smaller percent of alpha-myosin heavy chain content (28 +/- 20, 23.5 +/- 13 and 12 +/- 10 versus 58 +/- 18%, p less than 0.01, p less than 0.01 and p less than 0.001, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Heart Valve Diseases/metabolism , Myocardium/pathology , Myosins/metabolism , Adult , Echocardiography , Female , Heart Atria/pathology , Humans , Immunoglobulin Heavy Chains/metabolism , Male , Middle Aged , Mitral Valve/physiopathology , Myosins/classification
17.
C R Acad Sci III ; 305(4): 79-82, 1987.
Article in French | MEDLINE | ID: mdl-2957027

ABSTRACT

The atria produce several peptides that have natriuretic and vasoactive properties, collectively called atrial natriuretic factor. All these peptides share a single messenger ribonucleic acid, the amount of which greatly increases in the rat left ventricle when the latter is submitted to chronic volume overload. Using the molecular hybridization technique and a desoxyribonucleic acid probe complementary to the atrial natriuretic factor messenger ribonucleic acid, we now report that a very important increase in the amount of this messenger ribonucleic acid is also observed in rat ventricle at at the compensatory stage of a pressure overload induced cardiac hypertrophy. This result suggests that the pressure overload hypertrophied rat ventricle also has the potential to itself regulate it's loading conditions via the regulation of extracellular fluid volume and vascular resistance.


Subject(s)
Atrial Natriuretic Factor/genetics , Cardiomegaly/physiopathology , Myocardium/metabolism , RNA, Messenger/metabolism , Animals , Heart/anatomy & histology , Heart Ventricles/metabolism , Organ Size , RNA, Messenger/genetics , Rats , Rats, Inbred Strains
18.
Circ Res ; 59(5): 551-5, 1986 Nov.
Article in English | MEDLINE | ID: mdl-2948733

ABSTRACT

Cardiac hypertrophy due to a chronic hemodynamic overload is accompanied by isoformic changes of two proteins of the thick filament of the sarcomere, myosin, and creatine phosphokinase. We have looked for isoactin changes, using deoxyribonucleic acid probes complementary to alpha-skeletal and alpha-cardiac actin messenger ribonucleic acids. Three groups of rats were studied at various days after application of a pressure overload (2-4 days, n = 13, 8-15 days, n = 5, and 30-40 days, n = 7) and were compared to control animals (n = 11). Whereas alpha-skeletal actin messenger ribonucleic acids were hardly detectable in the normal hearts (0.6 +/- 0.16%), they accumulated significantly in the first 4 days after the aortic stenosis (4.6 +/- 3.1%, p less than 0.001 vs. controls) and then slowly declined (8-15 days, 3.2 +/- 1.7% and 30-40 days, 1.6 +/- 0.6%, p less than 0.05 and NS vs. controls). This figure is similar to that observed in 8-day-old rats (2.27 +/- 0.3%, p less than 0.01 vs. controls). We conclude that, in rat myocardium, the expression of messenger ribonucleic acids encoding the sarcomeric actins is altered at the onset of a pressure overload hypertrophy. Although the physiological significance of isoactin changes is unknown, our results show that the thin filament participates as well as the thick filament in the response of cardiac muscle to new functional requirements.


Subject(s)
Actins/analysis , Cardiomegaly/metabolism , Myocardium/analysis , RNA, Messenger/analysis , Animals , Animals, Newborn , Male , Nucleic Acid Denaturation , Nucleic Acid Hybridization , Rats , Rats, Inbred Strains
19.
Fed Proc ; 45(11): 2573-9, 1986 Oct.
Article in English | MEDLINE | ID: mdl-2944766

ABSTRACT

Chronic overloading of the rat heart induces a cascade of adaptational events that compensate for the increase in work. At the myocardial level there are two types of adaptational mechanisms: qualitative, represented by the isomyosin changes leading to an improved efficiency; and quantitative, the hypertrophy. We present new approaches exploring possible adaptational changes at other levels within the myocardial cell. Studies of heart overload were performed either in young rats with experimental aortic stenosis or in humans with chronic compensatory hypertrophy. By means of double immunofluorescence labeling of isolated myocytes with anti-V1 and anti-V3 myosin immunoglobulins, we showed that the shift from high- to low-ATPase isomyosins occurs rapidly after aortic stenosis (2-3 days). Cardiac myocytes were shown to be poor in tubulin but a microtubule pattern was clearly visualized by an immunofluorescence approach. Their role in the onset of adaptational processes after aortic stenosis in not yet clear. On the other hand, we showed that in humans, contrary to small rodents, the adaptational process at the isomyosin level is very small or nonexistent.


Subject(s)
Aortic Valve Stenosis/physiopathology , Heart/physiopathology , Animals , Aortic Valve Stenosis/metabolism , Calcium-Transporting ATPases/metabolism , Homeostasis , Humans , Isoenzymes/metabolism , Male , Myocardial Contraction , Myocardium/metabolism , Myosins/metabolism , Rats , Rats, Inbred Strains
20.
Eur Heart J ; 5 Suppl F: 211-7, 1984 Dec.
Article in English | MEDLINE | ID: mdl-6085308

ABSTRACT

Cardiac overload is associated with two different changes in gene expression: an increase in overall protein synthesis leading to hypertrophy, and at least two isoenzymic redistributions affecting myosin and creatine kinase. This preliminary report was an attempt to study the cardiac genome in this model. Total RNA (ribonucleic acid) was prepared by a combination of the guanidine-ethanol and phenol procedures. A DNA (deoxyribonucleic acid)-, t(transfer)-RNA-free preparation containing non-degraded 28 and 18 S rRNA and 3% poly A+-m (messenger) RNA was obtained. The poly A+mRNA isolated on an oligo (dT) cellulose column had an average nucleotide length of 1300 to 1800 and its c (complementary) DNA was 600 to 1400 base pairs. The first analysis of the kinetics of hybridation revealed a complex pattern which could be described by division into three components. Northern blot and dot blot using a recombinant cDNA plasmid complementary to myosin heavy chain or to actin mRNA (a gift from A. Weydert and M. Buckingham) indicated the presence of these two mRNA, with the former being frequently degraded. After aortic stenosis, both the content and the concentration of total RNA and poly A+mRNA increased in parallel and peaked by the 4th day at +35%. This is the first suggestion that the control of gene expression is transcriptional in this model.


Subject(s)
Cardiomegaly/metabolism , DNA, Recombinant , Gene Expression Regulation , Genes , Poly A/metabolism , RNA, Messenger/metabolism , Animals , Base Sequence , Creatine Kinase/genetics , Kinetics , Male , Myocardium/metabolism , Myosins/genetics , Nucleic Acid Hybridization , RNA/metabolism , Rats , Rats, Inbred Strains , Transcription, Genetic
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