Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Cardiac development”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,243 records · Page 69Linked to original sources
PubMed2006

Cardiac-specific elevations in thyroid hormone enhance contractility and prevent pressure overload-induced cardiac dysfunction.

Thyroid hormone (TH) is critical for cardiac development and heart function. In heart disease, TH metabolism is abnormal, and many biochemical and functional alterations mirror hypothyroidism. Although TH therapy has been advocated for treating heart disease, a clear benefit of TH has yet to be established, possibly because of peripheral actions of TH. To assess the potential efficacy of TH in treating heart disease, type 2 deiodinase (D2), which converts the prohormone thyroxine to active triiodothyronine (T3), was expressed transiently in mouse hearts by using the tetracycline transactivator system. Increased cardiac D2 activity led to elevated cardiac T3 levels and to enhanced myocardial contractility, accompanied by increased Ca(2+) transients and sarcoplasmic reticulum (SR) Ca(2+) uptake. These phenotypic changes were associated with up-regulation of sarco(endo)plasmic reticulum calcium ATPase (SERCA) 2a expression as well as decreased Na(+)/Ca(2+) exchanger, beta-myosin heavy chain, and sarcolipin (SLN) expression. In pressure overload, targeted increases in D2 activity could not block hypertrophy but could completely prevent impaired contractility and SR Ca(2+) cycling as well as altered expression patterns of SERCA2a, SLN, and other markers of pathological hypertrophy. Our results establish that elevated D2 activity in the heart increases T3 levels and enhances cardiac contractile function while preventing deterioration of cardiac function and altered gene expression after pressure overload.

Animals↗
PubMed2005

Vascular but not cardiac remodeling is associated with superoxide production in angiotensin II hypertension.

OBJECTIVE: Angiotensin (Ang) II increases reactive oxygen species (ROS), decreases nitric oxide (NO) bioavailability and promotes cardiovascular remodeling. ROS have been identified as critical second messengers of the trophic responses by Ang II. In rats with Ang II-induced hypertension, we investigated the role of ROS in cardiac hypertrophy as well as the remodeling of aortas and mesenteric (resistance) arteries. METHODS: Sprague-Dawley rats received Ang II (0.7 mg/kg per day by mini-pump, n = 7) or vehicle (n = 7) for 5 days. Endothelium-dependent relaxation to acetylcholine (EDR) in aortas was determined in organ baths and in mesenteric resistance vessels in a pressurized myograph. Superoxide (O2) production was measured by lucigenin chemiluminescence, laser-confocal fluorescence microscopy (LCM) and NADPH oxidase assay. RESULTS: Ang II-treated rats developed hypertension (183 +/- 3 versus 138 +/- 4 mmHg, P < 0.05), increased aortic O2 (50%), aortic hypertrophy (12%) and impaired EDR. Mesenteric arteries manifested impaired EDR, increased NADPH oxidase activity (356%) and eutrophic inward remodeling (decreased lumen diameter and increased wall/lumen ratio). However, although Ang II-treated rats developed cardiac hypertrophy (13%), this was not accompanied by an increase in cardiac O2, as measured by lucigenin, LCM or NADPH oxidase assay. On the other hand, cardiac calcineurin, a molecule that promotes cardiac hypertrophy linked to Ang II, was increased by 40% (52 +/- 8 versus 33 +/- 5 pmol/min per mg protein, P < 0.05). CONCLUSION: These studies demonstrate that the role of ROS in Ang II-induced vascular remodeling differ across vascular territories. Although in conduit and resistance vessels, vascular hypertrophy and endothelial dysfunction are linked to increased ROS production, cardiac hypertrophy is not. Instead, cardiac hypertrophy is associated, at least in part, with an increase in calcineurin. These studies unveil novel mechanisms that may play an important role in the pathogenesis of cardiac and vascular injury in hypertension.

Angiotensin II↗
PubMed2004

A novel transmembrane MSP-containing protein that plays a role in right ventricle development.

We have identified and characterized a gene, Mospd3 on mouse chromosome 5 using gene trapping in ES cells. MOSPD3 is part of a family of proteins, including MOSPD1, which is defined by the presence of a major sperm protein (MSP) domain and two transmembrane domains. Interestingly Mospd3 is mammalian specific and highly conserved between mouse and man. Insertion of the gene trap vector at the Mospd3 locus is mutagenic and breeding to homozygosity results in a characteristic right ventricle defect and neonatal lethality in 50% of mice. The phenotypic defect is dependent on the genetic background, indicating the presence of genetic modifier loci. We speculate that the further characterization of Mospd3 will shed light on the complex genetic interactions involved in cardiac development and disease.

Amino Acid Sequence↗
PubMed2001

Novel cell lines promote the discovery of genes involved in early heart development.

Clonal cell lines representing early cardiomyocytes would provide valuable reagents for the dissection of the genetic program of early cardiogenesis. Here we describe the establishment and characterization of cell lines from the hearts of transgenic mice and embryos with SV40 large T antigen expressed in the heart-forming region. Ultrastructure analysis by transmission electron microscopy showed the primitive, precontractile nature of the resulting cells, with the absence of myofilaments, Z lines, and intercalated disks. Immunohistochemistry, RT-PCR, Northern blots, and oligonucleotide microarrays were used to determine the expression levels of thousands of genes in the 1H and ECL-2 cell lines. The resulting gene-expression profiles showed the transcription of early cardiomyocyte genes such as Nkx2.5, GATA4, Tbx5, dHAND, cardiac troponin C, and SM22-alpha. Furthermore, many genes not previously implicated in early cardiac development were expressed. Two of these genes, Hic-5, a possible negative regulator of muscle differentiation, and the transcription enhancing factor TEF-5 were selected and shown by in situ hybridizations to be expressed in the early developing heart. The results show that the 1H and ECL-2 cell lines can be used to discover novel genes expressed in the early cardiomyocyte.

Actins↗
PubMed2005

Atrioventricular conduction disturbances in a young patient with Fabry's disease without other signs of cardiac involvement.

A 30 year-old male patient with a history of Fabry's disease, was referred to hospital with symptoms of dizziness, hypotension and weakness. Fabry's disease had been diagnosed 2 years before, based on angiokeratoma and hypohidrosis on physical examination and complete lack of alpha-galactosidase A on laboratory examination. The ECG on admission demonstrated sinus bradycardia, with a poor response to atropine administration. Echocardiograms on admission and 2 years before were normal, as well as Holter ambulatory ECG recording. Subsequent electrophysiological study demonstrated mild AV conduction disturbances at a site proximal to His, and the patient was simply advised to be regularly followed up. It can therefore be concluded that even young patients with Fabry's disease and normal echocardiograms might develop cardiac symptoms due to AV conduction abnormalities.

Adult↗
PubMed2003

Cardiac electrophysiological phenotypes in postnatal expression of Nkx2.5 transgenic mice.

Nkx2.5 is a conserved homeodomain (HD) containing a transcription factor essential for early cardiac development. We generated several mutations modeling some patients with congenital heart disease. Transgenic mice (tg) expressing the wildtype Nkx2.5 under beta-myosin heavy chain (MHC) promoter died during the embryonic stage. However, tg mice expressing this mutation under beta-MHC promoter (beta-MHC-TG(I183P)), the wildtype Nkx2.5 (alpha-MHC-TG(wild)), and a putative transcriptionally active mutant (carboxyl-terminus deletion, alpha-MHC-TG(DeltaC)) under alpha-MHC promoter showed postnatal lethal heart failure. Given the profound atrioventricular conduction abnormalities we recently demonstrated in beta-MHC-TG(I183P) mice, the aim of this study was to determine whether alpha-MHC-TG(wild) and alpha-MHC-TG(DeltaC) mutant mice display similar cardiac electrophysiological phenotypes. Surface ECG recordings and in vivo electrophysiology studies were performed in alpha-MHC-TG(wild) mice and controls at 6 weeks of age, and in alpha-MHC-TG(DeltaC) mice and controls at 10 weeks of age. Ambulatory ECG recordings in alpha-MHC-TG(wild) and controls were obtained using an implantable radiofrequency telemetry system. PR prolongation and atrioventricular nodal dysfunction were detected in alpha-MHC-TG(wild) and alpha-MHC-TG(DeltaC) mice. Bradycardia and prolonged PR interval were seen in ambulatory ECG of alpha-MHC-TG(wild) mice compared to controls. Several alpha-MHC-TG(wild) mice died of bradycardia. Fetal and neonatal mutant Nkx2.5 expression causes severe cardiac conduction failure. Postnatal overexpression of nonmutant (wild) Nkx2.5 also causes conduction abnormalities, although the onset is after the neonatal stage. Bradycardia and AV conduction failure may contribute to the lethal heart failure and early mortality.

Animals↗
PubMed2000

The role of proteinases in angiogenesis, heart development, restenosis, atherosclerosis, myocardial ischemia, and stroke: insights from genetic studies.

The development of novel gene technologies in mice has provided an elegant tool to identify gene products that are causally linked to certain physiologic processes as well as the pathogenesis of numerous disorders. Using these techniques, three major proteolytic systems -- the plasminogen, the matrix metalloproteinase (MMP) and the coagulation systems -- have been shown to be involved in cardiovascular diseases, which still constitute the leading cause of death in Western societies. This overview summarizes the role of these proteolytic systems in angiogenesis, arterial stenosis, allograft transplant stenosis, vein graft stenosis, atherosclerosis, myocardial infarction, cardiac development and ischemic stroke and discusses possible therapeutic implications.

Coronary Artery Disease↗
PubMedDate not supplied

[Leponex, 10 years after -- a clinical review].

Clozapine was one of the major advances in the treatment of schizophrenia since the introduction of the classic antipsychotic agent chlorpromazine in the 1950s. Over the past 10 years, clozapine has become the reference compound for the development of new antipsychotics, and new drugs have been developed which have also claimed atypical status. The indications of clozapine were recently extended to Psychosis in Parkinson's disease and harmonized in the European Union. This provides the opportunity to update the data on clozapine in the treatment of schizophrenia. In this article we review current clinical evidence in schizophrenia to address the following issues: 1) Efficacy in refractory/positive symptoms: a systematic and critical analysis of 14 double-blind clinical trials in comparison with both standard and novel antipsychotics show consistent findings in favour of clozapine, with all but three of the reports demonstrating superiority. The review of studies allow us to say little about the predictors of treatment response, time to clozapine response and about the impact of clozapine on the quality of patients'life and longer-term outcome. Treatment options for clozapine non-responders are reviewed. 2) Risk of EPS: clozapine is considered to have a minimal risk of EPS and in all studies where a valid methodology was used, a clear superiority over the other neuroleptics is demonstrated. It is pointed out that, if the prevalence and incidence of EPS with clozapine is low, it is not zero. All the studies assessing clozapine treatment for TD have major methodological limitations, so no final conclusion can be drawn. 3) Efficacy for primary and secondary negative symptoms and neurocognitive effects: the data of clinical studies where negative symptoms scales were used favour clozapine in terms of improvement. However most of the studies were carried out in populations with predominantly positive symptoms. With regard to the need to distinguish primary and secondary symptoms, data are conflicting regarding the benefit of clozapine. Due to the lack of studies with a valid methodology, no definitive conclusion can be drawn about the efficacy on clozapine on the deficit syndrome and on neurocognitive disorders. 4) Impact on suicide risk: 4 out of 6 retrospective studies provide evidence for the ability of clozapine therapy to reduce suicidal behaviour. The results of a recent randomized, parallel-group study designed to compare clozapine versus olanzapine in preventing suicide attempts seems to confirm this hypothesis. We also address the tolerability and safety data, especially haematologic, comitial, cardiovascular and metabolic side-effects. The effectiveness of blood monitoring for the management of neutropenia and agranulocytosis demands that the recommendations are strictly followed. The use of clozapine at doses higher than 600 mg daily should follow published recommendations, in order to minimize the risk of seizures; these include anticonvulsant regimens based on blood levels. With regard to the cardiovascular mortality, if clozapine therapy has negligible effects on QT interval, its association with potential fatal myocarditis cannot be excluded in young patients who should be investigated if they develop cardiac symptoms in the first weeks of treatment. Available data support the notion that the frequency of bodyweight gain is high with several new antipsychotics, including clozapine. Potential long term effects of bodyweight gain on mortality and morbidity have to be taken into consideration. The pharmacological mechanisms underlying the "unique clozapine profile" is discussed. Clozapine remains the only antipsychotic with efficacy at relatively low D2 receptor occupancy. The pharmacogenetic and pharmacokinetic aspects are also reviewed. Finally, the place of clozapine in the current treatment of schizophrenia is highlighted to inform the development of guidelines for clinical management.

Antipsychotic Agents↗
PubMed2002

Effects of aging and subsequent exercise training on gene expression of endothelin-1 in rat heart.

Endothelin-1 (ET-1) is produced by endothelial cells and cardiac myocytes. ET-1 has potent positive inotropic and chronotropic effects on heart and induces myocardial cell hypertrophy. We investigated whether gene expression of ET-1 in rat hearts is altered by aging and subsequent exercise training. We also investigated whether gene expression of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), which participate in some pathological cardiac conditions, in the rat hearts is altered by aging and subsequent exercise training. We studied mRNA expression of ET-1, ANP and BNP in hearts of sedentary young rats (Sedentary young; 4 months old), sedentary aged rats (Sedentary aged; 23 months old), and swim-trained aged rats (Trained aged; 23 months old, swimming training for 8 weeks). The left ventricle weight mass index for body weight and left ventricular end-diastolic dimension were significantly higher in the Trained aged group compared with the Sedentary aged group. These results showed that Trained aged rats developed cardiac hypertrophy with improvement of cardiac function. The mRNA expression of ET-1 in the heart was significantly higher in Sedentary aged group compared with Sedentary young group, and was significantly higher in the Trained aged group compared with the Sedentary aged group. The mRNA expression of ANP and BNP in the heart was significantly higher in Sedentary aged group compared with Sedentary young group, and was significantly higher in the Trained aged group compared with the Sedentary aged group. The present results show that mRNA expression of ET-1 in the heart is increased by aging, and that the mRNA expression is further increased by exercise-induced cardiac hypertrophy, suggesting that ET-1 in the heart may participate in these physiological cardiac adaptations.

Aging↗
PubMed2004

Human mesenchymal stem cells form Purkinje fibers in fetal sheep heart.

BACKGROUND: We have investigated the usefulness of a model of cardiac development in a large mammal, sheep, for studies of engraftment of human stem cells in the heart. METHODS AND RESULTS: Adult and fetal human mesenchymal stem cells were injected intraperitoneally into sheep fetuses in utero. Hearts at late fetal development were analyzed for engraftment of human cells. The majority of the engrafted cells of human origin formed segments of Purkinje fibers containing exclusively human cells. There were no differences in engraftment of human mesenchymal stem cells from adult bone marrow, fetal brain, and fetal liver. On average, 43.2% of the total Purkinje fibers in random areas (n=11) of both ventricles were of human origin. In contrast, approximately 0.01% of cardiomyocytes were of human origin. CONCLUSIONS: Human mesenchymal stem cells preferentially engraft at high levels in the ventricular conduction system during fetal development in sheep. These findings raise the possibility that stem cells contribute to normal development of the fetal heart.

Animals↗
PubMed2004

Varied clinical presentations of Vibrio vulnificus infections: a report of four unusual cases and review of the literature.

Vibrio vulnificus is a Gram-negative, motile, curved bacillus of the family Vibrionaceae that is a rare cause of gastroenteritis, septicemia, and wound infections in humans. V. vulnificus is halophilic, flourishes in warm temperatures, and is part of the bacterial flora of the marine environment. The location of our health care setting, on the Gulf of Mexico, has given us the opportunity to observe a wide variety of clinical presentations of infections caused by this organism. In the first case, a 27-year-old man struck by lightning while windsurfing was found pulseless in the water and was resuscitated. The patient subsequently developed cardiac arrhythmias, respiratory failure, and necrotizing fasciitis, blood cultures yielded V. vulnificus. After antibiotic therapy and several fasciotomies, the patient recovered. The second case was that of a 43-year-old Asian man employed as an oyster shucker who presented with complaints of redness, tearing, and photophobia of the right eye. The diagnosis of corneal ulcer secondary to V. vulnificus was made after culture of the right eye revealed the organism. The third case involved a 46-year-old man who presented with complaints of abdominal pain, nausea, chills, and bullous lesions on the lower extremities. He developed disseminated intravascular coagulation, and cultures of the lesions on his lower extremities showed V. vulnificus. Initially, the patient denied any exposure to raw seafood or seawater, but he eventually remembered eating raw oysters 3 days before his illness. The fourth case is that of a 32-year-old, human immunodeficiency virus-positive, hepatitis C-positive woman with cirrhosis who presented with productive cough, chills, fever, and red spots on her extremities and buttocks. Blood cultures revealed V. vulnificus and the patient was treated with antibiotics and improved clinically. These four cases illustrate the wide range of clinical presentations associated with this organism.

Adult↗
PubMed1994

Functional analysis of the connexin43 gene promoter in vivo and in vitro.

Connexin43 is the principal gap junction protein found in the mammalian heart. The regulation of connexin43 gene expression may be an important determinant of normal and altered cardiac development and electrophysiology. We constructed a series of chimeric luciferase reporter genes containing nested deletions from the human connexin43 gene (-2400 to -50 basepairs, relative to transcription initiation). The transcriptional activity of the chimeric genes was assayed in several cell types and systems, including rat cardiocytes in vitro and adult rat heart in vivo. In both systems, high levels of luciferase activity required at least 175 base-pairs of 5'-flanking sequence. Constructs including 2400 base-pairs of upstream sequence increased activity two-fold in vivo, but not in vitro. Chimeric genes were also assayed in cultured cardiac non-myocytes. This population of cells accumulates significant levels of connexin43 mRNA when propagated in vitro and promoter constructs were correspondingly active. Elements within the proximal promoter may also confer tissue-specificity. Transfectional analysis of the SKHep1 cell line, which does not express connexin43, demonstrated reduced reporter gene activity, especially for the longest constructs. These studies begin to define the cis-acting elements of the connexin43 gene which regulate its strength and specificity of transcription.

Animals↗
PubMed2004

Near-field scanning fluorescence microscopy study of ion channel clusters in cardiac myocyte membranes.

Near-field scanning optical microscopy (NSOM) has been used to study the nanoscale distribution of voltage-gated L-type Ca2+ ion channels, which play an important role in cardiac function. NSOM fluorescence imaging of immunostained cardiac myocytes (H9C2 cells) demonstrates that the ion channel is localized in small clusters with an average diameter of 100 nm. The clusters are randomly distributed throughout the cell membrane, with some larger fluorescent patches that high-resolution images show to consist of many small closely-spaced clusters. We have imaged unstained cells to assess the contribution of topography-induced artifacts and find that the topography-induced signal is <10% of the NSOM fluorescence intensity. We have also examined the dependence of the NSOM signal intensity on the tip-sample separation to assess the contributions from fluorophores that are significantly below the cell surface. This indicates that chromophores > approximately 200 nm below the probe will have negligible contributions to the observed signal. The ability to quantitatively measure small clusters of ion channels will facilitate future studies that examine changes in protein localization in stimulated cells and during cardiac development. Our work illustrates the potential of NSOM for studying membrane domains and protein localization/colocalization on a length scale which exceeds that available with optical microscopy.

Animals↗
PubMed1997

A role for Sp and nuclear receptor transcription factors in a cardiac hypertrophic growth program.

During cardiac hypertrophy, the chief myocardial energy source switches from fatty acid beta-oxidation (FAO) to glycolysis-a reversion to fetal metabolism. The expression of genes encoding myocardial FAO enzymes was delineated in a murine ventricular pressure overload preparation to characterize the molecular regulatory events involved in the alteration of energy substrate utilization during cardiac hypertrophy. Expression of genes involved in the thioesterification, mitochondrial import, and beta-oxidation of fatty acids was coordinately down-regulated after 7 days of right ventricular (RV) pressure overload. Results of RV pressure overload studies in mice transgenic for the promoter region of the gene encoding human medium-chain acyl-CoA dehydrogenase (MCAD, which catalyzes a rate-limiting step in the FAO cycle) fused to a chloramphenicol acetyltransferase reporter confirmed that repression of MCAD gene expression in the hypertrophied ventricle occurred at the transcriptional level. Electrophoretic mobility-shift assays performed with MCAD promoter fragments and nuclear protein extracts prepared from hypertrophied and control RV identified pressure overload-induced protein/DNA interactions at a regulatory unit shown previously to confer control of MCAD gene transcription during cardiac development. Antibody "supershift" studies demonstrated that members of the Sp (Sp1, Sp3) and nuclear hormone receptor [chicken ovalbumin upstream promoter transcription factor (COUP-TF)/erbA-related protein 3] families interact with the pressure overload-responsive unit. Cardiomyocyte transfection studies confirmed that COUP-TF repressed the transcriptional activity of the MCAD promoter. The DNA binding activities and nuclear expression of Sp1/3 and COUP-TF in normal fetal mouse heart were similar to those in the hypertrophied adult heart. These results identify a transcriptional regulatory mechanism involved in the reinduction of a fetal metabolic program during pressure overload-induced cardiac hypertrophy.

Acyl-CoA Dehydrogenase↗
PubMed1987

Cardiac morphogenesis--recent research advances.

It has been demonstrated recently that a specific region of neural crest contributes cells to the septa of the outflow tract of the heart. Removal of this region of cardiac neural crest prior to migration from the neural fold results in persistent truncus arteriosus in chick embryos. Removal of other regions of cranial neural crest results in double outlet right ventricle. Since double outlet right ventricle is produced by manipulation of noncardiac neural crest, this malformation is thought to be an indirect rather than direct effect of neural crest ablation. The cranial neural crest forms the walls of all of the aortic arch arteries and it is proposed herein that flow abnormalities are produced in the pharyngeal region by injury to the neural crest. These abnormal hemodynamic characteristics influence heart development. Cardiac neural crest seeds the heart with parasympathetic postganglionic neurons as well as ectomesenchyme. Removal of the cardiac neural crest results in cardiac malformations because of the decreased ectomesenchymal cells. However, the neural population undergoes regeneration and so the innervation of malformed hearts is morphologically normal. The mechanism for this regeneration is not understood.

Animals↗
PubMed2003

The effects of self-efficacy promoting cardiac rehabilitation program on self-efficacy, health behavior, and quality of life.

BACKGROUND: Ischemic heart disease results from athesclerotic changes of the coronary artery. These changes are aggravated by hypercholesterolemia, smoking, obesity, lack of exercise, coronary-prone personality, and stress. Because these risk factors affect not only the prevalence of the ischemic heart disease but also recurrence of the disease, cardiac rehabilitation programs were introduced to help patients with ischemic heart disease reduce risk factors. Diverse cardiac rehabilitation programs are needed to motivate participation in cardiac rehabilitation and to enhance patients' quality of life. OBJECTIVES: To examine the effect of a self-efficacy promoting cardiac rehabilitation program on self-efficacy, health behavior and quality of life of patients with ischemic heart disease. METHODS: Data were collected from 45 hospitalized ischemic heart disease patients. Medical records were reviewed to obtain demographic and clinical characteristics. Data regarding self-efficacy, health behavior, and quality of life were obtained from interviews using structured questionnaires. The nonequivalent control group non-synchronized design was used to conduct this study. One session of conventional group education was given to patients in the control group while they were in the hospital. Patients in the experimental group participated in a newly developed cardiac rehabilitation program. It focused on strengthening self-efficacy with four self-efficacy sources - performance accomplishment, vicarious experiences, verbal persuasion and physical status using two individualized in-hospital education sessions and four weekly telephone counseling follow-up calls after discharge. RESULTS: Four weeks after discharge, the increment of total self-efficacy score was significantly higher in the experimental group than in the control group (p<.01). There was also a significant difference in the total quality of life scores increments between the two groups (p<.01). However, no significant changes were noted in the increments of total health behavior scores between the two groups. CONCLUSION: A cardiac rehabilitation program focusing on promoting self-efficacy was effective in improving self-efficacy, and quality of life of patients with ischemic heart disease.

Journal Article↗
PubMed2004

Overexpression of the catalytic subunit of protein phosphatase 2A impairs cardiac function.

Reversible protein phosphorylation is an essential regulatory mechanism in many cellular functions. In contrast to protein kinases, the role and regulation of protein phosphatases has remained ambiguous. To address this issue, we generated transgenic mice that overexpress the catalytic subunit alpha of protein phosphatase 2A (PP2A) (PP2Acalpha) in the heart driven by the alpha-myosin heavy chain promoter. Overexpression of the PP2Acalpha gene in the heart led to increased levels of the transgene both at RNA and protein levels. This was accompanied by a significant increase of PP2A enzyme activity in the myocardium. Morphological analysis revealed isles of necrosis and fibrosis. The phosphorylation state of phospholamban, troponin inhibitor, and eukaryotic elongation factor 2 was reduced significantly. The expression of junctional (calsequestrin) and free SR proteins (SERCA and phospholamban) was not altered. Whereas no increase in morbidity or mortality was noted, transgenic mice developed cardiac hypertrophy and reduced contractility of the heart, as well as cardiac dilatation as shown by biplane echocardiography. Taken together, these findings are indicative of the fundamental role of PP2A in cardiac function and imply that disturbances in protein phosphatases expression and activity may cause or aggravate the course of cardiac diseases.

Actins↗
PubMed1994

Gene encoding a novel murine tissue inhibitor of metalloproteinases (TIMP), TIMP-3, is expressed in developing mouse epithelia, cartilage, and muscle, and is located on mouse chromosome 10.

Remodeling of the extracellular matrix (ECM) is an essential component of normal development and is also involved in the pathogenesis of arthritis and the spread of cancer. The matrix metalloproteinases and their natural inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), play an important role in this context. We have isolated mouse cDNA clones encoding a novel member of the TIMP family, designated TIMP-3. We have assigned the Timp-3 locus to the [C1-D1] region of mouse chromosome 10 using both genetic and cytogenetic methods. The conceptual translation product of the Timp-3 cDNA shows a high degree of similarity with ChIMP-3, a recently cloned chicken metalloproteinase inhibitor, as well as significant structural similarity with the amino acid sequences of the previously isolated members of this family, TIMP-1 and TIMP-2. The pattern of expression of Timp-3 in the developing mouse embryo is distinct from that previously reported for Timp-1. Timp-3 is expressed in cartilage and skeletal muscle, in myocardium, in the skin, oral and nasal epithelium, in the newborn mouse liver, in the epithelium of some tubular structures such as the developing bronchial tree, oesophagus, colon, urogenital sinus, bile duct, in the kidney, salivary glands, and in the choroid plexus of the brain. The patterns of Timp-3 expression in surface epithelia and in the epithelial lining of many tubular organs suggests that TIMP-3 may be involved in regulating ECM remodeling during the folding of epithelia and during the formation, branching, and expansion of epithelial tubes. In the mouse placenta, expression is seen in the trophoblast, raising the possibility that TIMP-3 may be involved in regulating trophoblastic invasion of the uterus. We propose a role for TIMP-3 in musculoskeletal and cardiac development, in the morphogenesis of certain epithelial structures, and placental implantation.

Amino Acid Sequence↗