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J M Moalic

Publications and source records attributed to J M Moalic.

At least 37 records · Page 2Linked to original sources
PubMed1993

Cardiac hypertrophy and failure--a disease of adaptation. Modifications in membrane proteins provide a molecular basis for arrhythmogenicity.

Cardiac hypertrophy is the physiological adaptation of the heart to chronic mechanical overload. Cardiac failure indicates the limits of the process. Cardiac hypertrophy is only one example of biological adaptation and results from the induction of several changes in gene expression, mostly of the fetal type, including those coding for the myosin heavy chain or the alpha-subunit of the Na+,K(+)-ATPase. From a thermodynamic point of view, the decrease in Vmax allows the heart to produce a normal tension at a lower cost. This process results from changes both in the sarcomere and in the expression of certain membrane proteins. The decrease in calcium transient is determined by several changes in membrane proteins that result in a rather fragile equilibrium in terms of calcium homeostasis. Any abnormal input in calcium will have exaggerated detrimental consequences on a hypertrophied myocyte and may cause automaticity and arrhythmias or an exaggerated response to anoxia in terms of compliance.

Adaptation, Physiological↗
PubMed1992

The membrane proteins of the overloaded and senescent heart.

Cardiac hypertrophy which occurs during chronic mechanical overload is one of the numerous examples of biological adaptation to environmental requirements. As such, it is obtained at random by trial and error, and adaptation represents the sum of various modifications in gene expression, including the shift in isoform of myosin or in iso Na+, K+ ATPase, the decrease in beta-adrenergic and muscarinic receptors, ryanodine channels or SR Ca2+ ATPase densities and the unchanged density in Ca2+ current. Some of these changes are beneficial at the cellular level, but are finally detrimental for the organism as a whole, as is the slowing of Vmax. It was suggested that the calcium homeostasis of the hypertrophied cardiocyte was fragile and that this modified cell was less able to buffer the changes in the intracellular calcium, thus providing a biological basis for the arrhythmogenicity of the hypertrophied heart. These various modifications may provide a new key for future pharmaceutical research.

Adaptation, Physiological↗
PubMed1989

Signal and adaptational changes in gene expression during cardiac overload.

Chronic cardiac overload stimulates various quantitative and qualitative mechanisms of adaptation, some of them being species-specific. The signals responsible for these changes in gene expression are still speculative, nevertheless early modifications of the microtubular network have been reported. Soon after overload an increased expression of various genes coding for regulatory proteins has also been observed, this includes various oncogenes and the genes of several heat-shock proteins. Hypertrophy only, is non species-specific and is adaptational because it both multiples the number of contractile units and it lowers wall stress. The slowing of the shortening velocity allows the heart to produce normal tension, at a lower cost, and has different biological explanations depending on the species. In small rodent ventricles, the main but probably not the unique, determinant of this physiological parameter is an isomyosin shift from a high ATPase activity form V1 to a low activity form V3, discovered in our laboratory in 1979. This shift has a transcriptional origin and also occurs in atria in every mammalian including humans; nevertheless it has not been evidenced in the ventricles of humans, dog, cat or guinea-pig. In these species it is necessary to take into account other mechanisms, namely those involved intracellular calcium movements. The number of total, and possibly active, calcium channels is normal in rat overloaded heart suggesting that their synthesis is activated commensurate to the development of hypertrophy. The situation is more complex for other sarcolemma proteins such as the beta-adrenergic system and the Na+, K(+)-ATPase. For the latter there is presently some evidence that an isoenzymatic shift is likely to occur, at least in rats.

Adaptation, Physiological↗
PubMed1989

Phenylephrine, vasopressin and angiotensin II as determinants of proto-oncogene and heat-shock protein gene expression in adult rat heart and aorta.

The expression of two oncogenes (conc) c-myc and c-fos, coding for nuclear proteins which play a regulatory role in growth and differentiation, and of two genes coding for two heat shock proteins (HSP) 68 (molecular weight 68,000) and 70 (molecular weight 70,000), which have a protective function during stress, have been investigated by Northern blot analysis of the total RNA, extracted from adult rat ventricle and aorta. (1) The two onc transcripts are absent from these tissues but their expression can be enhanced by a pretreatment with cycloheximide. (2) The HSP70 is, in part, constitutive, while HSP68 is not; both are thermo-inducible in an isolated coronary perfused rat heart. (3) The four messenger RNA (mRNA) are expressed in both ventricles and aorta, 1 or 2 hours after i.p. injection of 6 mg/kg phenylephrine or 12 IU/kg of vasopressin. (4) They are also induced by a continuous or discontinuous injection of angiotensin II (7.5 micrograms/kg per min) for 1-2 h, but only in the aorta. The lack of ventricular response to angiotensin II in rat ventricles has been attributed to the lack of angiotensin II receptors in this tissue. This indicates that, in addition to mechanical factors, circulating hormones which have in common the use of the phosphoinositol pathway, may activate the expression of genes coding for regulatory proteins. This may play a role in the genesis of both ventricular and aortic hypertrophy.

Angiotensin II↗
PubMed1988

Coronary flow as a determinant of c-myc and c-fos proto-oncogene expression in an isolated adult rat heart.

Chronic cardiac overload induces quantitative and qualitative changes of the phenotype which finally adapt the myocardium to its new functional requirements (Swynghedauw, 1986). It has been proposed that both stretch and enhanced isometric tension could trigger these modifications (Peterson and Lesch, 1972), but until now no real messenger has been found. In a search for signals which may account for these changes, we decided to investigate the expression of two proto-oncogenes, c-fos and c-myc, coding for nuclear proteins (review in Adamson, 1987) because several of their properties are consistent with their possessing a role in the transduction of extracellular growth signals to the cell interior. We report here that, in adult rat heart, expression of the c-fos and c-myc proto-oncogene was both sequentially and transitorily increased when, in a beating heart but not in an arrested heart, the coronary flow (and/or pressure) was augmented. This was studied in an isolated, coronary perfused heart preparation, a model in which the initial conditions of a cardiac overload may be mimicked in such a way that protein synthesis is stimulated by increasing the coronary perfusion pressure (Kira et al., 1984).

Animals↗
PubMed1988

[Augmentation of the expression of c-myc and c-fos oncogenes as a function of the mechanical activity of the isolated adult rat heart].

c-myc and c-fos oncogenes encode nuclear DNA binding proteins, and are involved in both growth regulation and differentiation. Using the molecular hybridization technique and DNA probes complementary to c-myc and c-fos mRNA, we report an increase in c-myc and c-fos expression level in the isolated beating adult rat heart with reference to the arrested isolated heart. This suggests a causal relationship between mechanical activity of the heart and c-myc and c-fos expression. It evidences for the first time a messenger between mechanical factor and adaptational changes in the phenotype which occurs at the beginning of cardiac hypertrophy.

Animals↗
PubMed1987

Messenger RNA content and complexity in normal and overloaded rat heart.

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.

Animals↗
PubMed1984

Myosin heavy chain and actin fractional rates of synthesis in normal and overload rat heart ventricles.

The rates of synthesis (in per cent per day) of the total protein (ks) and myosin heavy chains (ke HC) and actin (ke A), isolated by preparative electrophoresis from myofibrils prepared in a relaxing medium, have been measured in rat heart ventricles after a continuous infusion of 50 microCi of (14C) Tyrosine (0.5 ml/h during 6 h). Normal values, in the sham-operated group, were for ks 19%, ke HC 23% and ke A 11%. Two to 4 days after an abdominal aortic stenosis there was an increase in the specific radioactivity of free plasma and intra-cellular tyrosine and of protein-bound tyrosine. The rate of synthesis also increased up to 37% for ks, 41% for ke HC and 21% for ke A but the ratio ke HC/ke A remained unchanged. We conclude that the normal heterogeneity of the rate of synthesis of the two main contractile proteins, at least when measured on myofibrils free from easily releasable myofilaments, was unmodified by cardiac overload, although both of these rates of synthesis were stimulated.

Actins↗
PubMed1984

Messenger RNA content and complexity in normal and overloaded rat heart: a preliminary report.

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.

Animals↗
PubMed1984

[Characterization of total RNA, messenger poly(A)+ RNA and homologous complementary DNA in experimental cardiac hypertrophy].

Two biological modifications are observed during adaptation of cardiac tissue to work overload: an increase in total protein synthesis and a redistribution of myosin isoenzymes. These modifications suggest that changes in DNA transcription are involved in the early response of cardiac tissue to overload. Results are reported in this paper that show a parallel increase in total and polyadenylated RNA content and concentration in cardiac overloaded tissue in the rat. The characterization of cardiac poly (A)+ mRNA by mRNA X cDNA hybridization and the identification of specific mRNAs with recombinant plasmid cDNAs are given in this report as preliminary results.

Animals↗
PubMed1981

Protein synthesis during systolic and diastolic cardiac overloading in rats: a comparative study.

The rate of protein synthesis in the heart of normal rats and those with either abdominal aortic stenosis (AS), aortic incompetence (AI) or both AS + AI, was measured by a continuous infusion of (3H) lysine. The total protein synthesis rate in normal animals averaged 13% per day. During bot types of hypertrophy, there was an increased incorporation of (3H) lysine into proteins without any significant change in the specific radioactivity of free lysine in the tissue. After 6 days of stenosis, the synthesis rate of total mixed RNA-free proteins of the two ventricles had increased to 24.8% per day, and returned to normal by the second week. After aortic incompetence, the average fractional rate of protein synthesis was near normal during the first week and a significant increase (up to 28% per day) was observed only after 2 to 3 weeks. Protein synthesis returned to normal by the first month. The rate of protein synthesis was normal in the final stage of cardiac overloading comparable to that obtained when both stenosis and incompetence had been combined. These results were in agreement with in vitro studies which showed a normal protein synthesis rate during the first hours of volume overloading It was hypothesised that the trigger for protein synthesis in both conditions was a decline in efficiency due to a change in the speed of shortening.

Animals↗
PubMed1981

[Total and contractile protein synthesis during experimental cardiac hypertrophy].

The fractional turnover rate of the total protein extracted from cardiac rat ventricles has been measured by the continuous infusion flow technique in unanesthesized animals using 3H-lysine as a marker. This turnover rate approximated 12 p. 100 per day, doubled after aortic stenosis or aortic incompetence, and reached a peak within a week after stenosis and 2 weeks after incompetence. The fractional turnover rate of actin and myosin heavy-chains has been measured by the same technique using 14C-tyrosine as a marker and preparative gel electrophoresis to isolate the protein. This turnover rate approximated 22 and 9 p. 100 per day for myosin and actin, respectively, and doubled 4 days after aortic stenosis. It is suggested that a drop in contraction efficiency triggered protein synthesis in cardiac overloading.

Animals↗
PubMed1979

[Action of erucic and palmitic acids on rat cardiac myoblasts in primary cell culture. An ultrastructural study (author's transl)].

Primary cultures of beating myocardial cells of neonatal rat are taken in order to observe the ultrastructural modifications caused by certain long chain fatty acids (erucic acid C22 : 1 and palmitic acid C16 : 0). Reference cultures are established and observed at the same time as the others. The eurcic acid create an intense steatosis, on the opposite palmitic acid does not. On the contrary the transormations of certain cellular organites such as mitochondria, dictyosomes, rough endoplasmic reticulum and ribosomes are observed in both cases.

Animals↗
PubMed1977

[Rest and active potentials of dissociated rat heart cells in culture].

Intracellular investigation of bioelectrical properties is performed on cultivated rat myocardial cells. Electrophysiological parameters of cells dissociated from rat myocardium are very similar to those of in vivo cells. Fast sodium channels are found to be fonctional. Spontaneous arrhythmia are recorded from some impaled cells.

Action Potentials↗