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PubMed2026

CD109 exhibits a dynamic expression pattern in coronary endothelium and endocardial-derived valve mesenchyme during heart development with preserved morphogenesis following endothelial-specific deletion.

BACKGROUND: CD109 encodes a GPI-linked glycoprotein that acts as a signaling modulator in the TGF-β pathway. CD109 has emerged in several genome-wide association studies as linked to coronary artery disease, myocardial infarction, and angina pectoris. Heterozygous loss-of-function mutations in CD109 have also been reported in patients with congenital heart defects, suggesting potential developmental relevance, though CD109 has never been investigated in the context of cardiovascular development. We previously identified Cd109 upregulation in murine atrioventricular valves undergoing myxomatous degeneration following a reduction of epicardial-derived cells. Here, we characterize Cd109 expression in the murine cardiovascular system and assess its function during development using in vitro and in vivo approaches. RESULTS: We found that Cd109 is strongly expressed in the endothelium of the coronary vasculature and in endocardial-derived subpopulations in the atrioventricular valves. This expression persists through key stages in cardiovascular development. Western blotting and immunostaining confirm endothelial expression in heart and lung tissues. siRNA-mediated knockdown of CD109 in primary human endothelial cells led to dysregulation of vascular development pathways and decreased tube formation capacity. We generated endothelial-specific Cd109 knockout mice, eliminating Cd109 expression from heart and lung tissues without overt consequences for atrioventricular valve or coronary vascular morphogenesis during heart development. CONCLUSION: CD109 exhibits a highly dynamic spatiotemporal expression pattern during cardiovascular development, with enriched expression in coronary endothelial cells and endocardial-derived subpopulations in the valves. Despite this striking developmental expression pattern, previously reported human genetic associations with cardiovascular diseases, and endothelial-associated phenotypes following siRNA-mediated CD109 knockdown in a primary human endothelial cell line, endothelial/endocardial-lineage deletion of Cd109 did not produce overt abnormalities in atrioventricular valve or coronary vascular morphogenesis during embryonic development. Collectively, these findings identify CD109 as a useful marker of coronary endothelial and endocardial-derived valve cell populations and suggest that CD109 may function in a context-dependent or modulatory manner rather than as an essential regulator of cardiovascular morphogenesis under normal developmental conditions.

CD109↗
PubMed1999

Retinoid signaling required for normal heart development regulates GATA-4 in a pathway distinct from cardiomyocyte differentiation.

Vitamin A is essential for normal embryonic cardiogenesis. The vitamin A-deficient phenotype in the avian embryo includes an abnormal heart tube closed at the sinus venosus and the absence of large vessels that normally connect the embryonic heart to the developing circulatory system. In vitamin A-deficient embryos the expression of cardiomyocyte differentiation genes, including atrial-specific myosin heavy chain, ventricular-specific myosin, and sarcomeric myosins as well as the putative cardiomyocyte specification gene Nkx-2.5, is not altered. However, the expression of transcription factor GATA-4 is severely decreased in the heart-forming regions of vitamin A-deficient stage 7-10 embryos. Significantly, GATA-4 transcripts are completely lacking in the lateral mesoderm posterior to the heart, in the area of the developing cardiac inflow tract that later displays prominent morphological defects, including a closed nonseptated heart lacking a sinus venosus. The administration of retinol to the vitamin A-deficient embryo restores GATA-4 expression and completely rescues the vitamin A-deficient phenotype. Our results indicate that GATA-4 is a component of the retinoid-mediated cardiogenic pathway unlinked to cardiomyocyte differentiation, but involved in the morphogenesis of the posterior heart tube and the development of the cardiac inflow tract.

Animals↗
PubMed2005

The interaction effects of binary mixtures of benzene and toluene on the developing heart of medaka (Oryzias latipes).

The United States Environmental Protection Agency (USEPA) has pursued the estimation of risk of adverse health effects from exposure to chemical mixtures since the early 1980s. Methods used to calculate risk estimates of mixtures were often based on single chemical information that required assumptions of dose-addition or response-addition and did not consider possible changes in response due to interaction effects among chemicals. Full factorial designs for laboratory studies can produce interactions information, but these are expensive to perform and may not provide the information needed to evaluate specific environmentally relevant mixtures. In this research, groups of Japanese medaka (Oryzias latipes) embryos were exposed to binary mixtures of benzene and toluene as well as to each of these chemicals alone. Endpoint specific dose-response models were built for the hydrocarbon mixture under an assumption of dose-additivity, using the single chemical dose-response information on benzene and toluene. The endpoints included heart rate, heart rate progression, and lethality. Results included a synergistic response for heart rate at 72 h of development, and either additivity or antagonism for all other endpoints at 96 h of development. This work uses an established statistical method to evaluate the toxicity of an environmentally relevant mixture to ascertain whether interaction effects are occurring, thus providing additional information on toxicity.

Animals↗
PubMed1990

Changes in the expression of connexin 43, a cardiac gap junctional protein, during mouse heart development.

A cDNA probe coding for rat connexin 43 (Beyer et al., 1987), a gap junctional protein, was used to detect specific mRNA and estimate its relative abundance in mouse heart at different developmental stages: 11, 14 and 19 days post-coïtum (dpc); 1, 2 and 3 weeks post-partum (wpp), and at the adult stage. On Northern blots of total cellular RNA, a single 3.0 kb message was detected at all stages of development, and the differential intensities of labeling indicated developmental changes in mRNA abundance. mRNA levels were further investigated by dot-blotting. Densitometric analyses of dot-blot autoradiograms showed a five-fold increase of the mRNA level between 11 dpc and 1 wpp, then a gradual decrease until the adult stage where it reached a value close to that detected at 11 dpc. By comparison, myosin heavy chains and glycerldehyde-3-phosphate dehydrogenase mRNAs were found to peak at 3 wpp and 14 dpc, respectively. The presence and the relative abundance of connexin 43 were investigated at the same developmental stages as previously by immunoblotting of whole-ventricle fractions using antipeptide antibodies specific for this junctional protein. Quantitative data obtained from densitometric analyses of immunoblots showed that from 14 dpc to 1 wpp intensity of labeling of connexin 43 was roughly multiplied by a factor of 10. It peaked at 3 wpp before dropping to about 20% at the adult stage. The data obtained with both the cDNA probe and the antibodies were significant as shown by variance analyses. They suggest that expression of cardiac connexin 43 is developmentally-regulated: at the early stages of heart development the expression levels of the protein would seem to be mainly regulated by mRNA abundance; beyond 2 weeks after birth, the levels of connexin 43 would seem rather to depend upon its stability and/or the efficiency of the translation.

Amino Acid Sequence↗
PubMed1992

Early heart development in the chick embryo: effects of isotretinoin on cell proliferation, alpha-actin synthesis, and development of contractions.

Isotretinoin is a potent retinoic acid used in the treatment of skin disorders. Though very effective, it is teratogenic if administered during pregnancy, and its teratogenic effect may be related to the normal activity of retinoids as signalling molecules in the embryo. Although its exact mechanism of action is unknown, it has been suggested that it causes its characteristic pattern of defects that includes heart defects, by inhibiting the migration of neural crest cells. However, other effects on cells are known. We studied early cardiac cell proliferation using incorporation of bromodeoxyuridine (BrdU) and detection with a monoclonal anti-BrdU. Proliferation in heart tissue of whole embryo cultures was inhibited in medium with 10(-6) M isotretinoin to 62% of the control level in myocardium. We studied its effects in culture on precardiac explant development in the absence of the neural crests. Culture of precardiac mesodermal-endodermal explants revealed that development of heart vesicles from the mesoderm was little affected, but the development of heartbeat was inhibited depending on dose in the 10(-5) to 10(-7) M range. The effect on development of contractions was augmented in the presence of serum; it could be duplicated by all-trans-retinoic acid, and it was reversible. Synthesis of the alpha-actin isotype, analyzed by isoelectric focusing, was found to be inhibited or delayed. The results suggest multiple effects of retinoids on growth, morphogenesis, and differentiation of early cardiac tissue, and are discussed in relation to the potential role of retinoids in early embryogenesis.

Actins↗
PubMed1999

The cardiac homeobox gene Csx/Nkx2.5 lies genetically upstream of multiple genes essential for heart development.

Csx/Nkx2.5 is a vertebrate homeobox gene with a sequence homology to the Drosophila tinman, which is required for the dorsal mesoderm specification. Recently, heterozygous mutations of this gene were found to cause human congenital heart disease (Schott, J.-J., Benson, D. W., Basson, C. T., Pease, W., Silberbach, G. M., Moak, J. P., Maron, B. J., Seidman, C. E. and Seidman, J. G. (1998) Science 281, 108-111). To investigate the functions of Csx/Nkx2.5 in cardiac and extracardiac development in the vertebrate, we have generated and analyzed mutant mice completely null for Csx/Nkx2.5. Homozygous null embryos showed arrest of cardiac development after looping and poor development of blood vessels. Moreover, there were severe defects in vascular formation and hematopoiesis in the mutant yolk sac. Interestingly, TUNEL staining and PCNA staining showed neither enhanced apoptosis nor reduced cell proliferation in the mutant myocardium. In situ hybridization studies demonstrated that, among 20 candidate genes examined, expression of ANF, BNP, MLC2V, N-myc, MEF2C, HAND1 and Msx2 was disturbed in the mutant heart. Moreover, in the heart of adult chimeric mice generated from Csx/Nkx2.5 null ES cells, there were almost no ES cell-derived cardiac myocytes, while there were substantial contributions of Csx /Nkx2.5-deficient cells in other organs. Whole-mount &bgr;-gal staining of chimeric embryos showed that more than 20% contribution of Csx/Nkx2. 5-deficient cells in the heart arrested cardiac development. These results indicate that (1) the complete null mutation of Csx/Nkx2.5 did not abolish initial heart looping, (2) there was no enhanced apoptosis or defective cell cycle entry in Csx/Nkx2.5 null cardiac myocytes, (3) Csx/Nkx2.5 regulates expression of several essential transcription factors in the developing heart, (4) Csx/Nkx2.5 is required for later differentiation of cardiac myocytes, (5) Csx/Nkx2. 5 null cells exert dominant interfering effects on cardiac development, and (6) there were severe defects in yolk sac angiogenesis and hematopoiesis in the Csx/Nkx2.5 null embryos.

Animals↗
PubMed1998

Angiotensin AT1 receptor inhibition, angiotensin-converting enzyme inhibition, and combination therapy with developing heart failure: cellular mechanisms of action.

BACKGROUND: Past studies have shown that angiotensin-converting enzyme inhibition (ACEI) alone, angiotensin AT1 receptor blockade (AT1 block) alone, and combined treatment have differential effects on left ventricular (LV) function and geometry with developing congestive heart failure (CHF). The purpose of this study was to more carefully examine the cellular basis for these differential effects by using a model of pacing CHF. METHODS AND RESULTS: Pigs were randomly assigned to five groups: (1) rapid pacing (240 bpm) for 3 weeks (n = 9), (2) concomitant ACEI (benazeprilat, 0.187 mg/kg/day) and pacing (n = 9), (3) concomitant AT1 block (valsartan, 3 mg/kg/day) and pacing (n = 9), (4) concomitant ACEI and AT1 receptor blockade (benazeprilat/valsartan, 0.05/3 mg/kg/day, respectively) and pacing (n = 9), and (5) sham controls (n = 10). The dosage protocol was based on obtaining a 50% reduction in angiotensin I and angiotensin II pressor response with no significant effects on mean basal arterial pressure. In the pacing group, LV fractional shortening (LVFS) fell compared with control group (13.4+/-1.4 v 39.1+/-1.0%, P < .05). With AT1 block, LVFS was unchanged from pacing only. ACEI and combined treatment increased LVFS from pacing values (25.2+/-0.9 v 20.9+/-1.9%, respectively, P < .05). LV myocyte shortening velocity was reduced with chronic pacing compared with control group (27.2+/-0.6 v 58.6+/-1.2 microm/s, P < .05) and remained reduced with AT1 block (28.0+/-0.5 microm/s, P < .05). Myocyte shortening velocity increased with ACEI or combination treatment (36.9+/-0.7 v 42.3+/-0.8 microm/s, respectively, P < .05). Concomitant treatment with either ACEI or AT1 blockade normalized myocyte action potential duration. In the combined ACEI and AT1 blockade group, all parameters of the myocyte action potential were unchanged from control values. CONCLUSIONS: This study showed that combined ACEI and AT1 receptor blockade produced beneficial effects on myocyte contractility and electrophysiology when compared with either monotherapy alone and therefore may provide unique benefits with CHF.

Action Potentials↗
PubMed1981

Myocardial filopodia during early heart development.

We have compared the surface architecture of embryonic chick heart myocardial cells in two different grooves to see if any regional differences in surface features could be related to the developing anatomy of the myocardium. There was a qualitative difference in filopodia distribution. The developing interventricular sulcus completely lacked them whereas the ventral groove had numerous filopodia. The ventral groove is an anatomical landmark that remains after the precardiac anlage have fused. Thus, it is a post-fusion structure. This indentation "pops out" in later development and disappears. This region is therefore more compliant than the interventricular sulcus which doesn't pop out. Filopodia are therefore not associated with fusion or infolding per se but may be related to compliance.

Animals↗
PubMed2000

Mouse Ror2 receptor tyrosine kinase is required for the heart development and limb formation.

BACKGROUND: A mouse receptor tyrosine kinase (RTK), mRor2, which belongs to the Ror-family of RTKs consisting of at least two structurally related members, is primarily expressed in the heart and nervous system during mouse development. To elucidate the function of mRor2, we generated mice with a mutated mRor2 locus. RESULTS: Mice with a homozygous mutation in mRor2 died just after birth, exhibiting dwarfism, severe cyanosis, and short limbs and tails. Whole-mount in situ hybridization analysis showed that mRor2 was expressed in the branchial arches, heart and limb/tailbuds, in addition to the developing nervous system. The mutants had cardiac septal defects, mainly a ventricular septal defect. In addition, an examination of the skeletal systems revealed that the mutants had shorter limbs, vertebrae and facial structure, with a particular defect in their distal portions, and that almost no calcification was observed in their distal limbs. Histological examination showed abnormalities in the chondrocytes. CONCLUSIONS: Our findings suggest that mRor2 plays essential roles in the development of the heart and in limb/tail formation, in particular cardiac septal formation and ossification of distal portions of limbs and tails.

Animals↗
PubMed2005

Immunolocalization of chick periostin protein in the developing heart.

The process that cardiac cushions undergo to form the mature septa and valves of the adult heart is poorly understood. Periostin is an extracellular molecule that is expressed during cushion mesenchyme formation and throughout valvulogenesis. Once thought to be an osteoblast-specific factor, studies have shown this molecule is antiosteogenic. We have produced an antibody to chicken periostin and examined periostin's localization in the developing avian heart. This antibody recognized proteins from chick heart lysates around 90 kD molecular weight as predicted from the chick periostin mRNA and other periostin orthologs. Periostin immunolocalization was first evident as fibrous strands in the cushion mesenchyme. At HH25, periostin was detected on the basal surface of the trabecular endothelium and also on the endocardial epithelium of the atrioventricular cushion. We hypothesize that periostin may function in the organization of extracellular matrix molecules, providing cues necessary for attachment and spreading during the epithelial-to-mesenchymal transitions of the endocardial epithelium. Enhanced secretion of periostin in the region of delamination may directly or indirectly promote change in the myocardium that precedes or mediates delamination of the leaflet. At later stages of development (HH34-38), periostin was seen predominantly in the fibrous regions of the heart, such as the left atrioventricular valve (LAV), annulus, cardiac skeleton, and adventitia. We propose that periostin is induced by sheer stress and may be an essential molecular component for structures of the heart that undergo mechanical stress or tension during the cardiac cycle.

Animals↗
PubMed1995

Gradient of integrin alpha 6A distribution in the myocardium during early heart development.

The interactions of cells with extracellular matrices (ECM)1 are likely to be key determinants of embryonic development. Integrin adhesion receptors are ideally positioned to mediate some of these interactions since, in addition to mechanical adhesion, they transduce signals affecting cell proliferation and differentiation. We investigated expression of the integrin alpha 6 beta 1, a receptor for the ECM component, laminin in the early mouse embryo. An intriguing feature of this integrin is the existence of alpha 6 subunit isoforms. The A and B isoforms, which differ in the cytoplasmic tails, are expressed in cell-type specific fashion, and are likely to implement distinct cellular interactions with laminin. By RT-PCR, alpha 6B but not alpha 6A mRNA was detectable in embryo extracts from fertilized oocytes to 6.5 d.p.c. In subsequent stages, up to 11.5 d.p.c., alpha 6A mRNA was observed in mRNA extracts from whole embryos, but still in significantly lower amounts than alpha 6B. However, in extracts from isolated heart (9.5 to 11.5 d.p.c.), alpha 6A was the predominant alpha 6 isoform, while in extracts from other embryo parts no alpha 6A mRNA was detectable. At the protein level, immunostaining with specific antibodies showed alpha 6A protein in myocardial cells, at the early stage of heart tube development (8.5 d.p.c.). Localization to the myocardium was tightly restricted, since other structures of the embryonic heart, e.g., endocardium, or of the remaining embryo did not stain with anti-alpha 6A antibody. In the ventricular myocardium, expression of alpha 6A appeared more intense than in the subendocardial layer. Quantitation by confocal microscopy unveiled a gradient of expression of alpha 6A, increasing from the outer to the inner layers of the myocardium. This is the first demonstration of a gradient distribution of integrin molecules in a tissue, which appears to be directly connected with the process of organogenesis. The mechanism underlying our observations is not the turning on of a gene, rather it is the activation of a splicing mechanism that substitutes the cytoplasmic domain of a laminin receptor. Because integrin cytoplasmic domains are thought to be an important functional end of the molecule, this may be a mechanism to modulate cellular responses to laminin.

Animals↗
PubMed2003

Cellular disorganization and extensive apoptosis in the developing heart of mice that lack cardiac muscle alpha-actin: apparent cause of perinatal death.

Mice that lack cardiac muscle alpha-actin die during the perinatal period. Approximately 56% of mice that are homozygous null (-/-) for a functional cardiac alpha-actin gene do not survive to term, and the remainder generally die within 2 wk of birth. We found that there were neither morphologic differences nor differences in the extent of apoptosis between the mutant and normal hearts on embryonic day (E) 12 and E14 of development. However, apoptosis was greater in the hearts of homozygous null mice on E17 and postnatal day 1 when compared with wild-type hearts. The antiapoptotic factor Bcl-x/(L) was localized in regions adjacent to where apoptosis was detected. The distribution patterns of the apoptosis triggering protein p53 were similar to those of apoptotic cells. The growth of the prenatal and postnatal hearts of the cardiac alpha-actin-deficient mice was retarded, and the cytoplasmic filaments were disorganized. Although apoptotic cells were observed in both the atria and ventricles in the hearts of the homozygous null animals, the frequency was greater in the ventricles than in the atria. Our results indicate that the functional and structural disturbances in the mice with a homozygous lack of cardiac alpha-actin seem to be due to disorganized development of acto-myosin filaments in the affected cardiomyocytes. Other actin isoforms cannot compensate for the lack of cardiac alpha-actin, and this seems to induce apoptosis in defective cardiac myocytes, which are not able to cope with the increased workload in the perinatal phase.

Actin Cytoskeleton↗
PubMed2004

Saturated glucose uptake capacity and impaired fatty acid oxidation in hypertensive hearts before development of heart failure.

Abnormalities in energy metabolism may play an important role in the development of hypertensive heart failure. However, the transition from compensated hypertrophy to heart failure is not fully understood in terms of energy metabolism. In Dahl salt-sensitive (DS) and salt-resistant (DR) rats, myocardial fatty acid and glucose uptake values were determined using (131)I- or (125)I-labeled 9-methylpentadecanoic acid ((131)I- or (125)I-9MPA), and [(14)C]deoxyglucose ([(14)C]DG), fatty acid beta-oxidation was identified using thin-layer chromatography, and insulin-stimulated glucose-uptake was observed using a euglycemic hyperinsulinemic glucose clamp. Six-week-old rats were fed a diet that contained 8% NaCl, which resulted in development of compensated hypertrophy in DS rats at 12 wk of age and ultimately led to heart failure by 18 wk of age. Uptake of [(14)C]DG increased markedly with age in the DS rats, whereas (131)I-9MPA uptake was marginally but significantly increased only in animals aged 12 wk. The ratio of (125)I-9MPA beta-oxidation metabolites to total uptake in the DS rats was significantly lower (P < 0.05) at 12 (37%) and 18 (34%) wk compared with at 6 (45%) wk. Insulin increased [(14)C]DG uptake more than twofold in the DS rats at 6 wk, although this increase was markedly attenuated at 12 and 18 wk (11 and 8%, respectively). Our data suggest that in a hypertrophied heart before heart failure, fatty acid oxidation is impaired and the capacity to increase glucose uptake during insulin stimulation is markedly reduced. These changes in both glucose and fatty acid metabolism that occur in association with myocardial hypertrophy may have a pathogenic role in the subsequent development of heart failure.

Animals↗
PubMed2000

Programmed cell death in the developing heart: regulation by BMP4 and FGF2.

Programmed cell death, or apoptosis, plays an important role in embryonic development. To provide new insights into the role of programmed cell death in cardiac development, we examined the hearts of the murine embryos from E9.5 to postnatal day 3. Using terminal transferase-mediated dUTP nick end-labeling assays, apoptosis was detected in the endocardial cushions and myocardium from E11.5 to postnatal day 3 (P3). In the ventricular myocardium, more apoptotic cells were observed in the left than right ventricles throughout embryonic and early postnatal development. Apoptosis was also present in the trabeculae and papillary muscles of the ventricles. In the outflow tract, cell death was present in the endocardial cushions before they fuse to form the conotruncal septum (E11.5-E12. 5) and reached a peak intensity when the conotruncal septum formed (E13.5). In the atrioventricular (AV) endocardial cushions, cell death was detected in the fusion seam of the cushion tissues at E12. 5 and E13.5 during AV septation. When the patterns of apoptosis were compared with patterns of cell division, we found that programmed cell death occurred in the areas in the endocardial cushions and trabeculae where rates of cell proliferation were low. We also found that programmed cell death was regulated by the growth factors, BMP4 and FGF2, in vitro. BMP4 induced, whereas FGF2 inhibited, apoptosis in both endocardial cushions and ventricular myocardium. Overall, our observations show that there is apoptosis in the regions where fusion or remodeling of tissues occurs. We also show that cardiac programmed cell death can be influenced by growth factors.

Animals↗
PubMed2005

Myocardial heterogeneity in permissiveness for epicardium-derived cells and endothelial precursor cells along the developing heart tube at the onset of coronary vascularization.

The coronary vasculature develops from mesothelial and endothelial precursor cells (EPCs) derived from the proepicardial organ (PEO), which migrate over the heart to form the epicardium. By epithelial-mesenchymal transition (EMT), the subepicardium and epicardium-derived cells (EPDCs) are formed. EPDCs migrate into the myocardium, where they differentiate into smooth muscle cells and fibroblasts that stabilize the developing coronary vasculature and contribute to myocardial architecture. Complete PEO ablation results in embryonic lethality due to cardiac defects, including a looping disorder with a too wide inner curvature. To investigate the behavior of early coronary contributors, we analyzed normal quail embryos and found lumenized endothelial vessels in the subepicardium already at stage HH19. Furthermore, EPCs had penetrated into the myocardium of the inner curvature. To confirm that the myocardium of the inner curvature is specifically permissive for EPCs and to study early EPDC migration in more detail, chimeric chicken embryos harboring a quail PEO were analyzed. Lateral epicardial outgrowth and EMT were observed throughout, but migration into the myocardium was restricted to the inner curvature between HH19 and 22. The permissive myocardial area expanded to the atrium, atrioventricular canal, and trabeculated ventricle at stage HH23-24. In contrast, outflow tract myocardium was never found to be permissive for EPDCs and EPCs until HH30, not even when the quail PEO was attached directly onto it. We conclude that early coronary formation starts in the inner curvature and hypothesize that the presence of PEO-derived cells is essential for the maturation of the inner curvature and subsequent looping of the heart tube.

Animals↗
PubMed2003

Selective matrix metalloproteinase inhibition with developing heart failure: effects on left ventricular function and structure.

The matrix metalloproteinases (MMPs) are an endogenous family of proteolytic enzymes implicated to contribute to LV remodeling. However, broad-spectrum MMP inhibition (MMPi), particularly inhibition of interstitial collagenase (MMP-1), may not be clinically applicable. This study examined the effects of selective MMPi (sparing MMP-1) in a model of developing congestive heart failure. Pigs were randomly assigned to 3 groups: (1) rapid pacing for 3 weeks (240 bpm, n=10); (2) selective MMPi (20 mg/kg per day-PO;PGE7113313) and rapid pacing (n=12); and (3) controls (n=10). LV peak wall stress increased from controls with rapid pacing (140+/-6 versus 319+/-18 g/cm2; P<0.05) and was reduced with selective MMPi (208+/-9 g/cm2; P<0.05. Preload recruitable stroke work was reduced with rapid pacing (4.3+/-0.4 versus 1.2+/-0.2 dyne. cm/mm Hg; P<0.05) and was increased with selective MMPi (2.6+/-0.3 dyne. cm/mm Hg; P<0.05). Plasma norepinephrine increased by 6-fold in the rapid pacing group (P<0.05) and was reduced from untreated values with selective MMPi (P<0.05). At the myocardial level, myocyte cross-sectional area was increased with selective MMPi but fibrillar collagen volume fraction remained unchanged relative to control values. These results suggest that targeting a selective portfolio of myocardial MMP species for inhibition may provide a more rational therapeutic strategy in the setting of congestive heart failure.

Animals↗
PubMed1990

Changes in the expression of acetylcholinesterase molecular forms during rat heart development.

The development of the molecular forms of acetylcholinesterase was studied in rat heart during the perinatal period. In this study, the activity of acetylcholinesterase increased both per unit wet weight and per unit protein from post-conception day 14 to day 42. Additionally, the activity of atrial acetylcholinesterase per unit wet weight increased more rapidly after birth than that of ventricular acetylcholinesterase. The percent contribution of the various molecular forms to the total acetylcholinesterase pool in heart changed dramatically from the fetal to the neonatal period. This switch primarily consisted of a decrease in the ratio of the asymmetric to globular forms. Thus, the specific activity of globular forms increased while that of the asymmetric forms remained relatively stable. When the atria and ventricles were examined separately at 19 days post-conception, the percent contribution of the individual molecular forms in the two cardiac areas was different. The atria contained a pool of acetylcholinesterase forms similar to postnatal heart while the ventricles contained a pool of acetylcholinesterase forms with a lower globular to asymmetric ratio. Finally, this study showed that greater than half of the acetylcholinesterase pool was inhibited by incubating hearts from fetal rats with echothiopate iodide, suggesting that a large portion of acetylcholinesterase catalytic sites are externalized in fetal heart.

Acetylcholinesterase↗