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PubMed2005

Genetic manipulation and functional analysis of cAMP signalling in cardiac muscle: implications for a new target of pharmacotherapy.

Adenylate cyclase is a membrane-bound enzyme that catalyses the conversion of ATP into cAMP upon activation of cell-surface G-protein-coupled receptors, such as beta-adrenergic receptors, and initiates a cascade of phosphorylation reactions within the cell. Type 5 adenylate cyclase is a major isoform in the heart as well as in the striatum of the brain. Mice with a disrupted type 5 adenylate cyclase gene exhibited normal cardiac function under basal conditions, but a decreased response to isoprenaline stimulation. When mice were subjected to pressure overload stress with aortic banding, they developed cardiac hypertrophy, but with a significant reduction in the number of apoptotic cardiac myocytes as well as preserved cardiac function. When type 5 adenylate cyclase activity was inhibited pharmacologically, by the use of a novel P-site inhibitor with enhanced selectivity for this isoform, there were no changes in cardiac myocyte contractility, but the development of cardiac myocyte apoptosis induced by isoprenaline stimulation was effectively prevented. These results indicate that type 5 adenylate cyclase may serve as a better target of pharmacotherapy to prevent the development of cardiac myocyte apoptosis and thus failure in response to various cardiac stresses.

Adenylyl Cyclases↗
PubMed2000

A syndrome of tricuspid atresia in mice with a targeted mutation of the gene encoding Fog-2.

Tricuspid atresia (TA) is a common form of congenital heart disease, accounting for 1-3% of congenital cardiac disorders. TA is characterized by the congenital agenesis of the tricuspid valve connecting the right atrium to the right ventricle and both an atrial septal defect (ASD) and a ventricular septal defect (VSD). Some patients also have pulmonic stenosis, persistence of a left-sided superior vena cava or transposition of the great arteries. Most cases of TA are sporadic, but familial occurrences with disease in multiple siblings have been reported. Gata4 is a zinc-finger transcription factor with a role in early cardiac development. Gata4-deficient mice fail to form a ventral heart tube and die of circulatory failure at embryonic day (E) 8.5 (refs 6,7). Zfpm2 (also known as Fog-2) is a multi-zinc-finger protein that is co-expressed with Gata4 in the developing heart beginning at E8.5 (refs 8-10). Zfpm2 interacts specifically with the N-terminal zinc finger of Gata4 and represses Gata4-dependent transcription. Here we use targeted mutagenesis to explore the role of Zfpm2 in normal cardiac development. Zfpm2-deficient mice died of congestive heart failure at E13 with a syndrome of tricuspid atresia that includes an absent tricuspid valve, a large ASD, a VSD, an elongated left ventricular outflow tract, rightward displacement of the aortic valve and pulmonic stenosis. These mice also display hypoplasia of the compact zone of the left ventricle. Our findings indicate the importance of Zfpm2 in the normal looping and septation of the heart and suggest a genetic basis for the syndrome of tricuspid atresia.

Animals↗
PubMed1990

[Pathogenesis of congenital heart defects: fiction and truth].

This is a review based on a description of a standardized method (microdissection + SEM) for study of human and animal cardiac development. Two examples of the analytical approach are given. In the first one, concerning the establishment of contact between the aorta and the left ventricle, the previous assumptions for "vectorial bulbus rotation" are disproved by more precise observations of normal cardiac development. Aorta is not transferred into the left ventricle but is connected to it by means of a "conduit" (aortic vestibulum) delimited by the fusion of the conotruncus ridges. For the second example the multilevel-analysis of pathogenesis of conotruncus septum defects in Keeshond dogs was selected. At the organ level, hypoplasia of the right ventricle was diagnosed, accompanied by hypoplasia of conus cushions. Tissue-level analysis indicated that the major cause of these hypoplasias is a decreased relative volume of the myocardium. Further study at the cell level showed that the number of mesenchymal cells in certain parts of conotruncus cushions is also diminished. Combining these observations with what is known about the architecture of cell proliferation in the embryonic heart, allows to formulate a hypothesis on a selective lesion of the right proliferation center, as one of the main causes of the observed anomalies. Further progress towards the subcellular and molecular level will help to complete the pathway from a gene defect toward an organ defect.

Animals↗
PubMed1994

Calcium transients in single myocytes and membranous ultrastructures during the development of cardiac hypertrophy and heart failure in rats.

1. We examined changes in intracellular calcium transients of separated single myocytes from the right ventricle (RV) of the rat heart during the change from adaptation to maladaptation in response to a pressure overload. 2. Right ventricular hypertrophy (RVH) secondary to pulmonary hypertension was induced by a subcutaneous injection of monocrotaline. Developed tensions of the RV-free wall were decreased as RVH progressed. Single myocytes were separated from the RV during different stages of RVH. Fura-2/AM-loaded cells were field stimulated, and changes in calcium transients were measured by Olympus OSP-3 system. We also examined membranous ultrastructures (sarcoplasmic reticulum, mitochondria, surface caveolae) involved in calcium metabolism in the hearts using scanning electron microscopy. 3. We observed characteristic changes in calcium transients during the change from adaptation to maladaptation, and also found that one parameter (amplitude) of calcium transients appeared to be correlated with the changes in the number of sarcoplasmic reticulum. 4. These results provided some insights into the mechanism of calcium handling of hypertrophied heart in response to a pressure overload from adaptation to maladaptation especially when stimulatory frequency was high, and suggested that heart rate control is a very important factor for the treatment of patients with congestive heart failure.

Animals↗
PubMed2005

Slow and fast fiber isoform gene expression is systematically altered in skeletal muscle of the Sox6 mutant, p100H.

We have previously demonstrated that p100H mutant mice, which lack a functional Sox6 gene, exhibit skeletal and cardiac muscle degeneration and develop cardiac conduction abnormalities soon after birth. To understand the role of Sox6 in skeletal muscle development, we identified muscle-specific genes differentially expressed between wild-type and p100H mutant skeletal muscles and investigated their temporal expression in the mutant muscle. We found that, in the mutant skeletal muscle, slow fiber and cardiac isoform genes are expressed at significantly higher levels, whereas fast fiber isoform genes are expressed at significantly lower levels than wild-type. Onset of this aberrant fiber type-specific gene expression in the mutant coincides with the beginning of the secondary myotube formation, at embryonic day 15-16 in mice. Together with our earlier report, demonstrating early postnatal muscle defects in the Sox6 null-p100H mutant, the present results suggest that Sox6 likely plays an important role in muscle development.

Animals↗
PubMed2006

Insights into the genetic basis of congenital heart disease.

Cardiovascular malformations are the most common type of birth defect and result in significant mortality worldwide. The etiology for the majority of these anomalies remains unknown. Advances in the characterization of the molecular pathways critical for normal cardiac development have led to the identification of numerous genes necessary for this complex morphogenetic process. This work has aided the discovery of an increasing number of single genes being implicated as the cause of human cardiovascular malformations. This review summarizes normal cardiac development and outlines the recent discoveries of the genetic causes of congenital heart disease.

Aorta↗
PubMed1999

Functional analysis of human cardiac troponin by the in vitro motility assay: comparison of adult, foetal and failing hearts.

OBJECTIVE: Human cardiac development and heart failure are associated with altered troponin isoform expression and phosphorylation. As the functional effects of these changes in troponin are unknown, we isolated troponin from human foetal, normal adult and failing adult hearts and investigated their regulatory function. METHODS: Human cardiac troponin was assayed for regulatory function by in vitro motility assay and for protein content by SDS PAGE and immunoblotting. RESULTS: Human cardiac troponin regulated movement of actin-tropomyosin filaments over a bed of immobilised heavy meromyosin. At pCa 9, troponin from foetal and adult hearts reduced the fraction of filaments moving from 90% to less than 15% with a modest (25-30%) decrease in velocity. At pCa 5, troponin from normal adult hearts increased filament velocity by up to 47 +/- 3% with no change in the fraction of filaments moving. Foetal troponin increased velocity by only 4 +/- 6% and the effect of troponin from failing hearts was between these values at 31 +/- 5%. Foetal hearts showed different troponin I and T isoform expression compared with adult hearts. No differences in troponin isoform expression were demonstrated between normal and failing adult hearts. CONCLUSIONS: Functioning troponin and tropomyosin may be isolated from human heart and their properties investigated by in vitro motility assay. Both functional and isoform expression differences exist between foetal and adult cardiac troponin. The regulatory function of troponin from adults with end stage heart failure is different from normal adult troponin. These data suggest a role for altered troponin function in human cardiac development and heart failure.

Actins↗
PubMed2003

Sox6 regulation of cardiac myocyte development.

A mouse mutation (p100H/p100H) has been identified that is associated with cardioskeletal myopathy, heart block, delayed growth and early postnatal death. The gene that is disrupted in this mutation encodes the transcription factor Sox6. P19CL6 cells were used as an in vitro cardiomyocyte differentiation system and revealed that Sox6 is expressed exclusively when the cells are committed to differentiate to beating cardiac myocytes. We used the yeast two-hybrid system to identify the Prtb (Proline-rich transcript of the brain) protein as a Sox6 interactor, and subsequently confirmed the interaction by co-immunoprecipitation. Prtb expression in P19CL6 cells increased with differentiation to beating cardiomyocytes. Using the P19CL6 cells stably transfected with noggin, an antagonist of BMP (Bone Morphogenic Protein), we found that BMP expression is required for Sox6 expression in cardiomyocyte differentiation. Surprisingly, the expression of the alpha1c-subunit gene of the L-type Ca2+ channel decreased in P19CL6 cells as they differentiated to beating cardiac cells. Ectopic expression of Sox6 or Prtb alone in P19CL6 cells caused down-regulation of L-type Ca2+ alpha1c expression, but when Sox6 and Prtb were co-transfected to the cells, L-type Ca2+ alpha1c remained at basal levels. A similar relationship of Sox6 and L-type Ca2+ alpha1c expression was seen in vivo (comparing wild-type and p(100H)/p(100H) mutant mice). Thus, Sox6 is within the BMP pathway in cardiac differentiation, interacts with Prtb and may play a critical role in the regulation of a cardiac L-type Ca2+ channel.

Animals↗
PubMed2006

Inherited disposition to cardiac myxoma development.

Carney complex is a genetic condition in which affected individuals develop benign tumours in various tissues, including the heart. Most individuals with Carney complex have a mutation in the PRKAR1A gene, which encodes the regulatory R1alpha subunit of protein kinase A - a significant component of the cyclic-AMP signalling pathway. Genetically engineered mutant Prkar1a mouse models show an increased propensity to develop tumours, and have established a role for R1alpha in initiating tumour formation and, potentially, in maintaining cell proliferation. Ongoing investigations are exploring the intersection of R1alpha-dependent cell signalling with other gene products such as perinatal myosin, mutation of which can also cause cardiac myxomas.

Animals↗
PubMed2000

MMP-2 expression during early avian cardiac and neural crest morphogenesis.

Matrix metalloproteinase-type 2 (MMP-2) degrades extracellular matrix, mediates cell migration and tissue remodeling, and is implicated in mediating neural crest (NC) and cardiac development. However, there is little information regarding the expression and distribution of MMP-2 during cardiogenesis and NC morphogenesis. To elucidate the role of MMP-2, we performed a comprehensive study on the temporal and spatial distribution of MMP-2 mRNA and protein during critical stages of early avian NC and cardiac development. We found that ectodermally derived NC cells did not express MMP-2 mRNA during their initial formation and early emigration but encountered MMP-2 protein in basement membranes deposited by mesodermal cells. While NC cells did not synthesize MMP-2 mRNA early in migration, MMP-2 expression was seen in NC cells within the cranial paraxial and pharyngeal arch mesenchyme at later stages but was never detected in NC-derived neural structures. This suggested NC MMP-2 expression was temporally and spatially dependent on tissue interactions or differed within the various NC subpopulations. MMP-2 was first expressed within cardiogenic splanchnic mesoderm before and during the formation of the early heart tube, at sites of active pharyngeal arch and cardiac remodeling, and during cardiac cushion cell migration. Collectively, these results support the postulate that MMP-2 has an important functional role in early cardiogenesis, NC cell and cardiac cushion migration, and remodeling of the pharyngeal arches and cardiac heart tube.

Animals↗
PubMed2001

Rantes production during development of cardiac allograft vasculopathy.

BACKGROUND: RANTES (regulated on activation, normal T cell expressed and secreted) production has been shown to correlate with mononuclear cell recruitment and precede intimal thickening in cardiac allograft vasculopathy (CAV). However, the cells that produce RANTES in CAV are undefined. Therefore, in an MHC II-mismatched murine model of CAV, we sought to (1) define the cellular sources of RANTES and (2) determine the role of CD4+ lymphocytes in RANTES production during CAV development. METHODS: B6.CH-2bm12 strain donor hearts were transplanted heterotopically into wild-type (WT) or CD4 knockout (CD4KO) C57BL/6 mice (MHC II mismatch). No immunosuppression was used. Recipients were sacrificed at 7, 14, and 24 days. Intragraft RANTES gene expression and protein levels were determined with ribonuclease protection assay and ELISA, respectively. At days 7 and 24, RANTES production by graft-infiltrating cells was defined with intracellular RANTES staining and multicolor FACS analysis. Intimal thickening was quantitated morphometrically. In murine hearts and in six explanted human hearts with advanced CAV, RANTES was also localized immunohistochemically. RESULTS: NK, NKT, and gammadelta+ cells, in addition to CD4+, CD8+ lymphocytes, and CD11b+ macrophages, produced RANTES in early and late stages of CAV. RANTES-producing NK, NKT, and gammadelta+ cells tripled in number during CAV development; by day 24, NK and gammadelta+ cells each outnumbered CD4+ lymphocytes and CD11b+ macrophages. The presence of CD4+ lymphocytes was required for sustained RANTES production in allografts, which correlated with mononuclear cell recruitment and preceded intimal thickening. In murine and explanted human hearts with advanced CAV, RANTES immunolocalized with graft-infiltrating mononuclear cells and vessel wall cells. CONCLUSIONS: We present evidence that other cell types in addition to CD4+, CD8+ T lymphocytes, and CD11b+ macrophages contribute significantly to RANTES production in CAV. In this MHC II-mismatched murine model of CAV, sustained RANTES production requires CD4+ lymphocytes, correlates with mononuclear cell recruitment, and precedes intimal thickening. In experimental and human CAV, vessel wall cells may also produce RANTES. Interventions aimed at inhibiting RANTES production in CAV may need to target several types of cells, and neutralization of RANTES bioactivity may reduce mononuclear cell recruitment and CAV development.

Animals↗
PubMed2006

Filamin A (FLNA) is required for cell-cell contact in vascular development and cardiac morphogenesis.

Mutations in the human Filamin A (FLNA) gene disrupt neuronal migration to the cerebral cortex and cause cardiovascular defects. Complete loss of Flna in mice results in embryonic lethality with severe cardiac structural defects involving ventricles, atria, and outflow tracts, as well as widespread aberrant vascular patterning. Despite these widespread developmental defects, migration and motility of many cell types does not appear to be affected. Instead, Flna-null embryos display abnormal epithelial and endothelial organization and aberrant adherens junctions in developing blood vessels, heart, brain, and other tissues. Essential roles for FLNA in intercellular junctions provide a mechanism for the diverse developmental defects seen in patients with FLNA mutations.

Animals↗
PubMed2006

Cardiovascular changes after naloxone administration in propofol-sedated piglets during opioid overdose.

BACKGROUND: Naloxone is an opioid receptor antagonist. Even when used in modest doses, it has been associated with serious cardiopulmonary side-effects. In this experimental porcine study, we examined the cardiac effects of naloxone during an opioid overdose. METHODS: Cardiac parameters, changes in the left ventricular compliance and the magnitude of catecholamine release were evaluated in eight spontaneously breathing piglets under propofol sedation. Cardiac parameters were recorded every 30 s and transthoracic echocardiography was used for the continuous assessment of cardiac performance. Respiratory arrest was induced by morphine (8 mg/kg). Ten minutes after morphine administration, naloxone (80 microg/kg) was injected intravenously. Every 5 min, arterial blood gases were measured and, every 10 min, a sample for the analysis of plasma catecholamines was drawn. RESULTS: There were no statistically significant changes in left ventricular ejection fraction and no signs of pulmonary hypertension. There was a statistically significant increase in the mean arterial pressure immediately after naloxone administration and in norepinephrine concentration before naloxone administration. After naloxone administration, the plasma catecholamine levels decreased in all but one animal. Two animals developed cardiac arrest (pulseless electrical activity and ventricular fibrillation) shortly after receiving naloxone. Although they were both administered naloxone prematurely due to hypoxic bradycardia, naloxone could have contributed to the development of ventricular fibrillation. CONCLUSION: Naloxone did not cause changes in ejection fraction or mean pulmonary artery pressure in hypoxic and hypercarbic conditions. After naloxone administration, the plasma catecholamine levels returned to baseline in all but one animal, and two animals developed cardiac arrest.

Analgesics, Opioid↗
PubMed1979

The role of coronary artery injury and perfusion in the development of cardiac contusion secondary to nonpenetrating chest trauma.

Myocardial contusion secondary to nonpenetrating chest trauma can occur in the absence of any identifiable large vessel coronary artery occlusion or injury. It has also been reported in association with coronary artery atheromata, thrombosis, rupture, and fistula formation. After reviewing the clinical and experimental research literature, we conclude that myocardial contusion necrosis results from changes in perfusion of small vessels and the coronary microvasculature. Coronary arteriography and emergency coronary artery bypass surgery do not appear promising as therapeutic modalities to reduce myocardial necrosis in this condition. More appropriate therapeutic emphasis may result from research efforts to develop pharmacologic interventions to preserve contused myocardium similar to those currently being evaluated in the management of patients with ischemic myocardium secondary to coronary artery disease.

Adolescent↗
PubMed1975

The development of cardiac myxomas and papillary endocardial lesions from mural thrombus.

A morphologic study of 466 cardiac mural thrombi, 66 examples of nonbacterial thrombotic endocarditis, 25 myxomas, and 12 papillary endocardial lesions was performed. It appeared that three different sequences of organization of endocardial thrombi are possible. (1) Ordinary mural thrombi are converted into a flat, fibrous scar by fibroblast proliferation and collagen and elastic fiber deposition. (2) Papillary endocardial lesions develop from non bacterial thrombotic endocarditis as additional thrombus material is acquired in some foci and lost in others. No ingrowth of granulation tissue occurs at the base of these lesions. The thrombus material of the papillae is gradually replaced by fibrous tissue, and the lesion eventually is identical to a large Lambl's excrescence. (3) Myxomas enlarge in part as do the papillary endocardial lesions. In addition, their size increases as a result of influx into the myxoma of fluid from the basal granulation tissue. Although myxomas cannot be differentiated from ordinary mural thrombi on the basis of the cellular and ground substance components, their mode of development results in a distinctive appearance. The mature lesion is composed of three zones: a basal layer of small vascular channels, undifferentiated mesenchymal cells, and ground substance; a middle, acellular zone of ground substance; and a cortical layer of mesenchymal cells. The peculiar arrangement of endothelial cells and undifferentiated mesenchymal cells, the examples of apparent atrial wall invasion, and the cases of embolic "metastases" provide no conclusive evidence of neoplasia, since these features may also be seen with ordinary mural thrombi.

Aneurysm↗
PubMed2002

Increased tissue factor expression predicts development of cardiac allograft vasculopathy.

BACKGROUND: Cardiac allograft vasculopathy (CAV) limits the long-term success of cardiac transplantation. The incidence of CAV is increased in patients with elevated plasma levels of oxidized lipids or fibrin deposition within right heart biopsy (RHB) specimens. The present study investigated whether tissue factor (TF), the expression of which is regulated by oxidized lipids, is upregulated in patients with CAV. METHODS AND RESULTS: A TF score was developed to quantify TF expression in RHB specimens from 63 consecutive patients undergoing routine annual posttransplantation RHB and coronary angiography. In patients >2 years (3.0+/-0.8 years) posttransplantation (n=35), a high TF score was observed with greater frequency (75% versus 26%, P<0.004) in patients with CAV than those without CAV. In patients <2 years (0.87+/-0.48 years) posttransplantation (n=28) without evidence of CAV, the TF score was determined and patients were followed up prospectively. A high TF score had a positive predictive value of 78.6% for the development of CAV, and a low TF score had a negative predictive value of 100%. CONCLUSIONS: These data demonstrate that early TF expression predicts subsequent development of CAV. Increased TF expression could link the elevated levels of oxidized LDL and fibrin deposition known to precede CAV. These findings suggest that TF may play a role in the pathophysiology of CAV and could offer a potential prognostic tool and a novel target for the prevention of CAV, possibly with antioxidants or inhibitors of the TF pathway.

Adult↗
PubMed1975

Growth hormone in cardiac hypertrophy induced by nephrogenous hypertension.

Current evidence about the role of growth hormone in cardiac hypertrophy is ambiguous. The purpose of this investigation was to determine whether growth hormone was an important element in the cardiac hypertrophy induced by systemic hypertension. Male rats with either an intact hypophysis or a hypophysectomy were bilaterally adrenalectomized, and corticoids were replaced with exogenous deoxycorticosterone and hydrocortosone. Hypophysectomized rats were further treated with thyroxine, testosterone, and, where appropriate, bovine growth hormone. Selected groups of rats were made hypertensive by means of a surgical compression of the renal capsule which produced systemic hypertension. The magnitude of the hypertension was measured in awake rats by means of a tail plethysmograph and compressing tail-cuff. The hormone replacement program re-established systolic blood pressures in sham-operated, hypophysectomized rats to levels observed in intact-hypophysis, sham-operated rats. Thus, hypertensive, hypophysectomized rats obtained pressures above both hypophysectomized and intact-hypophysis, sham-operated rats. Hypertensive rats with an intact hypophysis and hypophysectomized rats with growth hormone developed cardiac hypertrophy. In spite of the hormone therapy, the above normal systemic blood pressures, and low mortality hopophysectomized rats without growth hormone did not develop cardiac hypertrophy.

Animals↗
PubMed2001

Differential NF-kappaB and IkappaB gene expression during development of cardiac allograft rejection versus CD154 monoclonal antibody-induced tolerance.

BACKGROUND: The Rel/NF-kappaB transcription factor pathway, regulated by IkappaB proteins, is considered central to immune responses, although there are surprisingly few in vivo data concerning alloresponses. METHODS: We undertook analysis of NF-kappaB and IkappaB mRNA intracardiac allograft expression, and NF-kappaB nuclear translocation, during acute rejection versus CD154 monoclonal antibody (mAb)-induced tolerance induction in fully MHC-disparate mice. RESULTS: Intragraft expression of all nine NF-kappaB and IkappaB genes increased during development of rejection, and nuclear translocation of p50, p52, and p65 was detected. CD154 mAb therapy decreased mRNA levels of all nine NF-kappaB and IkappaB genes, and impaired nuclear translocation of p50, p52, and p65 NF-kappaB proteins. However, prolonged survival could not be induced by CD154 mAb in p50- or p52-deficient allograft recipients, indicating an absolute requirement for expression of these genes in CD154 mAb-induced tolerance. CONCLUSIONS: We conclude that, whereas blanket approaches to NF-kappaB suppression are unlikely to be effective strategies for tolerance induction, a better understanding of the roles of individual NF-kappaB and IkappaB genes may allow development of more precise and effective therapies.

Animals↗