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Biomedical subjects

P Anversa

Publications and source records attributed to P Anversa.

At least 91 records · Page 5Linked to original sources
PubMed1995

Myocardial infarction and the myocyte IGF1 autocrine system.

To determine the effects of acute myocardial infarction on the extent and distribution of mural stress on surviving myocardial tissue, coronary artery occlusion was surgically produced in rats. Following haemodynamic measurements in vivo, the characteristics of cardiac anatomy were determined and found to consist of an increase in mid-chamber lumenal diameter and a decrease in wall thickness. The combination of these phenomena resulted in an eight-fold increase in diastolic wall stress on the remaining viable portion of the wall and severe impairment of left and right ventricular performance. Since insulin-like growth factor-1 (IGF1) and its receptor (IGF1R) are required for cell growth in vitro, the possibility was raised that an autocrine IGF1-IGF1R system may be present in vivo and may become activated in viable ventricular myocytes shortly after infarction. Therefore, the unaffected myocytes of the left ventricle were enzymatically dissociated and the expression of IGF1R and IGF1 mRNAs were measured at 12 h and at 1, 2-3, and 7 days after surgery. The level of IGF1R mRNA increased at 12 h and remained elevated at 1 and 2-3 days following coronary artery ligation. In addition, an increased level of IGF1R protein was found on these cells. This phenomenon was coupled with the enhanced expression of IGF1 mRNA in the muscle cells at all points. Thus, the marked elevation in ventricular loading after coronary occlusion may activate the IGF1-IGF1R autocrine system of the unaffected cells, modulating the cellular growth processes implicated in short-term ventricular remodelling of the infarcted heart.

Animals↗
PubMed1995

Alterations in energy metabolism of hypertrophied rat cardiomyocytes: influence of propionyl-L-carnitine.

Alterations in energy metabolism, reduced fatty acid oxidation, and cardiac carnitine content have been implicated in the evolution from compensated to decompensated cardiac hypertrophy. We determined high-energy nucleotide levels in hypertrophied quiescent cardiomyocytes isolated from rat hearts 4 weeks after banding of abdominal aorta. In hypertrophied quiescent cardiomyocytes, a decrease in ATP content (p = 0.03), and ratios of ATP/total adenine nucleotides and of ATP/ADP were observed, together with an increase in ADP. In addition, palmitate, but not glucose oxidation, was markedly reduced in hypertrophied myocytes. In the presence of 25 microM propionyl-L-carnitine (PLC) or L-carnitine (LC), palmitate oxidation was significantly stimulated in hypertrophied myocytes. The ATP/ADP ratio was significantly increased only with PLC. This effect was not due to an enhanced PLC uptake, since total PLC uptake was 50% lower than that of LC. Changes in the energy generating system of quiescent myocytes occur early in pressure overload hypertrophy, and these alterations can be attenuated by PLC.

Adenosine Diphosphate↗
PubMed1995

Myocyte performance during evolution of myocardial infarction in rats: effects of propionyl-L-carnitine.

To determine whether alterations in the mechanical properties and calcium transients of myocytes are important factors in the evolution of the postinfarcted heart, these physiological parameters were measured in the viable muscle cells of the left ventricle 6 h, 2-3 days, 1 wk, and 1 mo after coronary artery occlusion and the documentation of left ventricular failure. In addition, the effects of propionyl-L-carnitine (PLC) on shortening properties and calcium dynamics of single myocytes were established to demonstrate whether the potential increase in ATP generation by this intervention improved myocyte cell function. Myocardial infarction was associated with a progressive increase in length of the spared myocytes, whereas the changes in myocyte diameter were apparent only at the 1-mo interval. Mechanically, myocyte shortening was decreased 43% at 6 h, 34% at 2-3 days, 26% at 1 wk, and 41% at 1 mo after infarction. Similar abnormalities were noted in the velocity of myocyte shortening. Peak systolic calcium was decreased at all intervals after infarction. In contrast, diastolic calcium remained within control values. PLC was capable of ameliorating the mechanical behavior and calcium transients of myocytes, particularly 1 mo after infarction. Thus alterations in muscle cell performance may be important determinants in the development and progression of ischemic cardiomyopathy, and interventions improving myocyte contractility may interfere with the unfavorable outcome of the disease.

Animals↗
PubMed1995

Fibroblast proliferation during myocardial development in rats is regulated by IGF-1 receptors.

To determine whether the growth of cardiac fibroblasts during development is modulated by the insulin-like growth factor (IGF)-1 receptor (IGF-1R), the expression of IGF-1, IGF-2, and IGF-1R was determined in fibroblasts from fetal and postnatal hearts. The expression of proliferating cell nuclear antigen (PCNA) and DNA polymerase-alpha was also evaluated in combination with the estimation of DNA replication. In comparison with fetal hearts, at postnatal day 21, fibroblast expression of IGF-1R mRNA, IGF-2, PCNA, and DNA polymerase-alpha was reduced by 77, 70, 80, and 86%, respectively. Moreover, IGF-1R protein decreased by 48% at 21 days. Bromodeoxyuridine labeling decreased by 88 and 89% in the left and right ventricle, respectively, at this time. Two different antisense oligodeoxynucleotides to IGF-1R reduced DNA replication by 60 and 44% in fibroblasts in culture. In addition, this intervention markedly attenuated the growth response of fibroblasts to IGF-1 or serum. In conclusion, the IGF-1R system appears to play a major role in the regulation of fibroblast growth in the heart in vivo.

Animals↗
PubMed1995

Stretch-induced programmed myocyte cell death.

To determine the effects of loading on active and passive tensions, programmed cell death, superoxide anion formation, the expression of Fas on myocytes, and side-to-side slippage of myocytes, papillary muscles were exposed to 7-8 and 50 mN/mm2 and these parameters were measured over a 3-h period. Overstretching produced a 21- and a 2.4-fold increase in apoptotic myocyte and nonmyocyte cell death, respectively. Concurrently, the generation of reactive oxygen species increased 2.4-fold and the number of myocytes labeled by Fas protein 21-fold. Moreover, a 15% decrease in the number of myocytes included in the thickness of the papillary muscle was found in combination with a 7% decrease in sarcomere length and the inability of muscles to maintain stable levels of passive and active tensions. The addition of the NO-releasing drug, C87-3754, prevented superoxide anion formation, programmed cell death, and the alterations in active and passive tensions with time of overloaded papillary muscles. In conclusion, overstretching appears to be coupled with oxidant stress, expression of Fas, programmed cell death, architectural rearrangement of myocytes, and impairment in force development of the myocardium.

Animals↗
PubMed1995

Cellular basis of ventricular remodeling after myocardial infarction in rats.

The remodeling of the spared non-ischemic left ventricular myocardium after different time intervals from the occlusion of the left coronary artery was examined in rats. In the presence of large infarcts, ventricular failure developed two to three days after surgery, because of chamber dilation and thinning of the wall, resulting in an average 7.5-fold increase in diastolic stress on the surviving myocardium. Mural thinning of the ventricular wall remote from and bordering the infarction occurred through side-to-side slippage of myocytes and capillaries within the wall. Although an average hypertrophic growth of 22% of the spared myocytes has been found, this amount of hypertrophy was insufficient to restore normal myocardial function. Long-term cardiac restructuring after infarction was characterized by the persistence of chamber dilatation and thinning of the ventricular wall. In addition to the side-to-side slippage, lengthening of the myocytes was an important cause of ventricular changes. As the reactive hypertrophy of the unaffected ventricle was insufficient to re-establish the ratio of ventricular mass to chamber volume, the diastolic stress remained elevated and decompensated eccentric ventricular hypertrophy developed. The anatomical remodeling of the spared left ventricular myocardium is an important conditioning factor in the short- and long-term outcome of ischemic cardiomyopathy.

Animals↗
PubMed1995

Ventricular remodeling in global ischemia.

To determine the effects of chronic constriction of the left coronary artery on the function and structure of the heart, coronary artery narrowing was surgically induced in rats and ventricular pump performance, extent and distribution of myocardial damage, and the hypertrophic and hyperplastic response of myocytes were examined. Alterations in cardiac hemodynamics were found in all rats, but the characteristics of the physiological properties of the heart allowed a separation of the animals into two groups which exhibited left ventricular dysfunction and failure, respectively. Left ventricular hypertrophy occurred in both groups and was characterized by ventricular dilatation and wall thinning which were more severe in the failing animals. Multiple foci of myocardial damage across the wall were seen in all animals but tissue injury was more prominent in the endomyocardium and in failing rats. The anatomical and hemodynamic changes resulted in a significant increase in diastolic wall stress which paralleled the depression in ventricular performance. Myocyte cell loss and myocyte cellular hypertrophy were more severe with ventricular failure than with dysfunction. Finally, diastolic overload appeared to be coupled with activation of the DNA synthetic machinery of myocytes and nuclear mitotic division. In conclusion, a fixed lesion of the left coronary artery leads to abnormalities in cardiac dynamics with marked increases in diastolic wall stress and extensive ventricular remodeling in spite of compensatory myocyte cellular hypertrophy and hyperplasia in the remaining viable tissue.

Animals↗
PubMed1995

Down-regulation of the IGF-1 system parallels the attenuation in the proliferative capacity of rat ventricular myocytes during postnatal development.

BACKGROUND: Insulin-like growth factor-1 receptor (IGF-1R) and its ligand (IGF-1) have been implicated in the growth of several cell types, including ventricular myocytes. However, the growth-promoting effect of this pathway on myocyte hypertrophy and hyperplasia has not been determined. During early postnatal development, myocyte cell volume increases nearly 25-fold, and myocyte proliferation is markedly attenuated, so a progressive decrease in this signaling mechanism will indicate that the IGF-1-IGF-1R system is mostly involved in cell proliferation. Conversely, a continuous increase in the expression of IGF-1 and IGF-1R in myocytes with maturation will suggest its involvement in cellular hypertrophy. DESIGN: Myocytes were isolated from fetal rats and from rats at 1, 5, 11, 21, 35, and 60 days of age. Total RNA was extracted from these cells, and the expression of IGF-1, IGF-2, IGF-1R, and DNA polymerase alpha was measured by reverse transcriptase-PCR. IGF-1R mRNA levels were also determined by RNase protection assay, and the changes in IGF-1R protein were determined by the cross-linking technique. Finally, the expression of late growth-related genes was determined and compared with the fraction of muscle cells synthesizing DNA. These analyses were restricted to the left ventricular free wall and septum combined. RESULTS: Myocardial development was characterized by a progressive decrease in the expression of late growth-related genes in myocytes, which was particularly evident at 21 days after birth and persisted up to 2 months of age. The expression of IGF-2 in these cells decreased at birth, whereas the attenuation in IGF-1 mRNA became apparent a few days later during postnatal development. The induction of IGF-1R at the message and protein levels decreased by 11 days, and this phenomenon was more evident at the subsequent age intervals. Moreover, DNA synthesis in myocytes was sharply reduced at 21 days after birth. CONCLUSIONS: In conclusion, the decline in myocyte proliferation with cardiac development appears to be coupled with attenuation of the IGF-1-IGF-1R system, which may condition the changes in late growth-regulated genes, DNA replication, and cellular mitotic division in the myocardium.

Aging↗
PubMed1995

Myocyte nuclear mitotic division and programmed myocyte cell death characterize the cardiac myopathy induced by rapid ventricular pacing in dogs.

BACKGROUND: Observations in humans have raised the possibility that idiopathic dilated cardiomyopathy is characterized by myocyte cell loss and cell proliferation, which contribute to wall thinning and chamber dilation. Moreover, the mechanism of myocyte cell death in this patient population has been unclear. Because rapid ventricular pacing in dogs leads to a dilated myopathy that mimics the idiopathic form in man, this animal model was used to demonstrate whether myocyte nuclear mitotic division and programmed myocyte cell death occur in this setting. Additionally, the expression of proliferating cell nuclear antigen (PCNA) and Fas protein in myocytes was examined as a molecular indicator of the activation of the cell cycle and apoptotic cell death, respectively. EXPERIMENTAL DESIGN: Mongrel dogs were chronically instrumented for measurements of systemic hemodynamics and for left ventricular pacing. At sacrifice, myocardial samples were obtained for the estimation of the number of myocytes and interstitial cells showing mitosis and for the detection of DNA laddering. In addition, the number of myocyte nuclei exhibiting DNA strand breaks, as well as the frequency of myocytes labeled by PCNA and Fas protein, was determined. Finally, the distribution of nuclei in enzymatically dissociated myocytes was evaluated. RESULTS: Pacing-induced heart failure was characterized by DNA fragmentation and by 3700 myocytes per million cells undergoing apoptotic cell death. This phenomenon was accompanied by 11,000 cells per million expressing Fas protein. Concurrently, 22 and 17 myocytes and interstitial cells per million showed nuclear mitotic division, whereas no changes in the relative proportions of mononucleated and multinucleated myocytes were detected. Moreover, PCNA-labeled myocytes accounted for 40,000 cells per million. CONCLUSIONS: In conclusion, the induction of PCNA and Fas may be linked to the activation of myocyte proliferation and programmed cell death in the myocardium with rapid ventricular pacing, and these two cellular responses may play a key role in the development of the congestive dilated myopathy.

Animals↗
PubMed1994

Upregulation of IGF1, IGF1-receptor, and late growth related genes in ventricular myocytes acutely after infarction in rats.

To determine the effects of acute myocardial infarction on the expression of insulin-like growth factor1 (IGF1) and insulin-like growth factor1 receptors (IGF-1R) on the surviving myocytes of the left and right ventricles, large infarcts were produced in rats and the animals sacrificed 2 days later. Hemodynamic measurements of left and right ventricular pressures, +dP/dt and -dP/dt, and central venous pressure documented that coronary occlusion was associated with a severe impairment of cardiac function. By employing reverse transcriptase polymerase chain reaction (RTPCR), a low level of expression of IGF-1R mRNA was detected in myocytes from sham-operated rats. Acute myocardial infarction was found to enhance by nearly twofold the message for IGF-1R in viable myocytes biventricularly. Moreover, IGF1 mRNA increased 4.3-fold and 9.4-fold in left and right myocytes, respectively. In order to establish whether the upregulation of IGF1 and IGF-1R with infarction was coupled with induction of late growth related genes, which are known to be implicated in DNA replication and mitotic division, proliferating cell nuclear antigen (PCNA) and histone-H3 expression was assessed by Northern blot and RTPCR. The level of expression of PCNA mRNA was found to be increased 3.9-fold and 2.4-fold in left and right myocytes, respectively from infarcted hearts. Corresponding increments in histone-H3 mRNA were 25.5-fold and 5.3-fold, respectively. However, PCNA protein as detected by immunoperoxidase staining was restricted to a limited number of myocyte nuclei adjacent to the necrotic myocardium of the left ventricle. In conclusion, acute myocardial infarction is associated with enhanced expression of IGF1 and IGF-1R on stressed myocytes, and this phenomenon may activate genes essential for DNA synthesis, possibly affecting myocyte growth. These processes may be fundamental for the reconstitution of tissue mass and amelioration of function after infarction.

Animals↗
PubMed1994

Acute myocardial infarction leads to upregulation of the IGF-1 autocrine system, DNA replication, and nuclear mitotic division in the remaining viable cardiac myocytes.

Insulin-like growth factor-1 (IGF-1) and its receptor (IGF-1R) are required for cell proliferation in vitro, raising the possibility that an autocrine IGF-1-IGF-1R system may be present in vivo and become activated in the viable ventricular myocytes shortly after infarction. Therefore, following the in vivo documentation of left ventricular failure in rats subjected to occlusion of the left coronary artery, the unaffected myocytes of the left ventricle were enzymatically dissociated and the expression of IGF-1R and IGF-1 mRNAs were measured at 12 h and at 1, 2-3, and 7 days after surgery. The level of expression of IGF-1R mRNA increased at 12 h and remained elevated at 1 and 2-3 days following coronary ligation. In addition, an increased level of IGF-1R protein on these cells was found. This phenomenon was coupled with the enhanced expression of IGF-1 mRNA in the muscle cells at all intervals. Myocardial infarction was also accompanied by an upregulation of proliferating cell nuclear antigen (PCNA) mRNA in myocytes and the detection of PCNA protein in nearly 1% of the cells. Similarly, bromodeoxyuridine labeling demonstrated that a comparable number of myocytes was positively stained. Finally, mitotic images in myocytes were observed. Thus, the IGF-1R-IGF-1 autocrine system may modulate myocyte cellular hyperplasia in the failing heart.

Animals↗
PubMed1994

The IGF-1-IGF-1 receptor system modulates myocyte proliferation but not myocyte cellular hypertrophy in vitro.

In preliminary experiments it was established that the hypertrophic and hyperplastic responses of neonatal cardiac myocytes in culture were associated with enhanced expression of IGF-1 and IGF-1 receptors in these cells. Therefore, to determine the role of IGF-1 receptors on myocyte growth, cells were exposed to antisense oligodeoxynucleotides to IGF-1 receptor mRNA and the effects of this intervention on DNA synthesis, nuclear mitotic division, and changes in the number of myocytes were measured. Moreover, the influence of this procedure on ANF induction and myocyte cell volume was examined. Inhibition of the formation of IGF-1 receptors on myocytes suppressed DNA replication, mitosis, and cell proliferation. In contrast, the antisense treatment did not alter the expression of ANF in myocytes or cellular hypertrophy. Finally, IGF-1 stimulated DNA synthesis in myocytes cultured in serum-free medium, without inducing cellular hypertrophy. In conclusion, ligand activation of IGF-1 receptors on myocytes appears to be coupled with cell proliferation, whereas myocyte cellular hypertrophy seems to be independent from this effector pathway.

Animals↗
PubMed1994

Myocyte nuclear and possible cellular hyperplasia contribute to ventricular remodeling in the hypertrophic senescent heart in humans.

OBJECTIVES: The present investigation was designed to evaluate the growth reserve capacity of the aged and senescent myocardium. BACKGROUND: Aging affects the ability of the heart to sustain alterations in ventricular loading, and this phenomenon may be coupled with attenuation of the hypertrophic reaction of the myocardium. However, because myocyte cellular hyperplasia has been documented experimentally in the old heart, a similar adaptation may also occur in humans and play a role in this process. METHODS: The changes in number and size of ventricular myocytes were measured quantitatively in pathologic hearts of elderly subjects. Morphometric methodologies were applied to the analysis of 13 hypertrophic hearts obtained at autopsy from patients 80 +/- 4 (mean +/- SD) years old. An identical number of nonhypertrophic hearts collected from subjects 76 +/- 7 years old were used as control hearts. RESULTS: A 71% increase in left ventricular weight was associated with a 33% increase in average myocyte cell volume per nucleus and a 36% augmentation in the total number of myocyte nuclei in the ventricular myocardium. However, a 55% increase in right ventricular weight was the result of a 59% increase in the aggregate number of myocyte nuclei, with no change in myocyte cell volume. These cellular processes were associated with a 95% and 83% enlargement of the myocardial interstitium in the left and right ventricle, respectively. CONCLUSIONS: Myocyte nuclear and possibly cellular hyperplasia appear to be the prevailing growth mechanism of the overloaded aging myocardium. Proliferation of myocyte nuclei and connective tissue accumulation are the major determinants of ventricular remodeling in the hypertrophic senescent heart.

Aged↗
PubMed1994

Alterations in angiotensin II receptor mediated signal transduction shortly after coronary artery constriction in the rat.

OBJECTIVE: The aim of the study was to determine the effect of coronary artery constriction on the density of angiotensin II receptors and on the effector responses coupled with these receptors on myocytes one week after surgical induction of coronary artery stenosis in rats. METHODS: After induction of coronary artery stenosis and following the estimation of global cardiac performance, myocytes were enzymatically dissociated and radioligand binding studies were performed. In addition, the isotonic contractile performance, cytosolic calcium transients, and angiotensin II stimulated inositol phosphate generation in myocytes were measured in the presence and absence of the angiotensin II receptor subtype antagonist losartan. RESULTS: After documenting left ventricular failure and right ventricular dysfunction, the expression and density of angiotensin II receptors in left ventricular myocytes were evaluated and found to be increased 3.1-fold and 4.1-fold, respectively. Corresponding increases in right ventricular myocytes were 3.6-fold and 4.5-fold. In contrast, the quantity of the regulatory protein Gq alpha was not altered in either ventricle. Angiotensin II did not increase the generation of total inositol phosphates in left and right ventricular myocytes at maximum stimulation. However, the threshold for the formation of inositol phosphates was lowered in left ventricular myocytes of coronary narrowed rats. Measurements of single cell mechanics indicated that angiotensin II stimulation markedly improved the depression in myocyte function biventricularly. This inotropic effect was coupled with the restoration of cytosolic calcium. CONCLUSIONS: The upregulation of angiotensin II receptors on myocytes in this model of global ischaemia may be a compensatory mechanism ameliorating myocyte contractility in an attempt to sustain ventricular pump function.

Angiotensin II↗
PubMed1994

Coronary artery constriction in rats affects the activation of alpha 1 adrenergic receptors in cardiac myocytes.

OBJECTIVE: To determine whether alpha 1 adrenergic receptor mediated myocyte contractility and growth are depressed acutely after non-occlusive coronary artery narrowing, the left coronary artery was constricted in rats and mechanical behaviour, cytosolic calcium, and regulation of alpha 1 adrenergic receptors were examined in myocytes seven days later. METHODS: Coronary artery stenosis was surgically induced in rats and following the estimation of global cardiac performance myocytes were enzymatically dissociated and radioligand binding studies were performed. In addition, the isotonic contractile performance, cytosolic calcium transients and noradrenaline stimulated inositol phosphate generation in myocytes were measured in the presence of WB 4101 or after chlorethylclonidine treatment. RESULTS: Estimations of cell mechanics in vitro established that peak shortening was decreased by 36% and 18% in left and right ventricular myocytes of coronary stenosed rats. Time to peak shortening was prolonged by 29% in left and 20% in right myocytes, whereas velocity of shortening was decreased by 27% in left myocytes. These alterations were associated with increases in cell length and width, indicative of myocyte hypertrophy. In addition, coronary stenosis was accompanied by reductions in the expression of alpha 1a and alpha 1b receptor subtypes in myocytes. alpha 1 Adrenergic receptor density and noradrenaline stimulated phosphoinositol turnover were decreased by 30% and 34% in left myocytes. alpha 1a Adrenergic receptor subtype mediated cytosolic calcium concentration and myocyte mechanical performance were also impaired in left myocytes only. The alpha 1a adrenergic receptor subtype antagonist WB 4101 abolished noradrenaline stimulated inositol phosphate generation in myocytes, whereas chlorethylclonidine at large doses only partially inhibited this response. CONCLUSIONS: In conclusion, coronary narrowing leads to defects in the regulation of alpha 1 adrenergic receptors on myocytes which are coupled with attenuation in the transmission of signals, possibly affecting myocyte cell function and ongoing reactive cellular hypertrophy.

Adrenergic alpha-Antagonists↗
PubMed1994

Myocyte cellular hypertrophy is responsible for ventricular remodelling in the hypertrophied heart of middle aged individuals in the absence of cardiac failure.

OBJECTIVE: The aim was to measure changes in the numbers and size of ventricular myocytes in human hearts with marked ventricular hypertrophy and no clear signs of cardiac failure, to determine whether myocyte cellular hypertrophy is the only factor involved in the increase in cardiac mass. METHODS: Morphometric techniques were applied to estimate the number of myocyte nuclei per unit volume of myocardium which, in combination with the determination of the volume percent of myocytes, allowed the computation of the average myocyte cell volume per nucleus and total number of myocyte nuclei in the ventricles. Subsequently, the volume fraction of replacement fibrosis in the tissue was assessed and absolute component volumes in the ventricles obtained. RESULTS: Eight hypertrophied human hearts, weight 561(SD 68) g, were collected at necropsy from hypertensive patients who died from non-cardiac causes and were compared with eight normal hearts, weight 387(37) g, obtained from healthy individuals who also died from non-cardiac causes. With cardiac hypertrophy, left and right ventricular weight increased by 53% and 57%, whereas myocyte cell volume increased by 112% and 84%, respectively. The disproportion between the increase in ventricular weight and the increase in myocyte volume was due to a 30% and 16% loss in left and right ventricular myocytes following hypertensive hypertrophy. Myocyte loss also provoked a 319% and a 188% increase in the amount of replacement fibrosis in the left and right ventricular myocardium. These tissue and cellular processes resulted in an expansion in ventricular mass which exceeded the thickening of the wall so that an increase in cavitary volume occurred in both ventricles. CONCLUSIONS: Myocyte cellular hypertrophy is responsible for ventricular hypertrophy in hypertensive cardiomyopathy in its compensated stage. Myocyte loss precedes the impairment in ventricular pump function and may be implicated in the initiation of ventricular maladaptation.

Cardiomegaly↗