Forced expression of the cell cycle inhibitor p57Kip2 in cardiomyocytes attenuates ischemia-reperfusion injury in the mouse heart

<p>Abstract</p> <p>Background</p> <p>Myocardial hypoxic-ischemic injury is the cause of significant morbidity and mortality worldwide. The cardiomyocyte response to hypoxic-ischemic injury is known to include changes in cell cycle regulators. The cyclin-dependent kinase inhibitor <it>p57</it>^{<it>Kip</it>2}is involved in cell cycle control, differentiation, stress signaling and apoptosis. In contrast to other cyclin-dependent kinase inhibitors, p57^Kip2expression diminishes during postnatal life and is reactivated in the adult heart under conditions of cardiac stress. Overexpression of <it>p57</it>^{<it>Kip</it>2}has been previously shown to prevent apoptotic cell death <it>in vitro </it>by inhibiting stress-activated kinases. Therefore, we hypothesized that <it>p57</it>^{<it>Kip</it>2}has a protective role in cardiomyocytes under hypoxic conditions. To investigate this hypothesis, we created a transgenic mouse (<it>R26loxpTA-p57</it>^<it>k</it>/+) that expresses p57^Kip2specifically in cardiac tissue under the ventricular cardiomyocyte promoter <it>Mlc2v</it>.</p> <p>Results</p> <p>Transgenic mice with cardiac specific overexpression of <it>p57</it>^{<it>Kip</it>2}are viable, fertile and normally active and their hearts are morphologically indistinguishable from the control hearts and have similar heart weight/body weight ratio. The baseline functional parameters, including left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LVEDP), LVdp/dt_max, heart rate (HR) and rate pressure product (RPR) were not significantly different between the different groups as assessed by the Langendorff perfused heart preparation. However, after subjecting the heart <it>ex vivo </it>to 30 minutes of ischemia-reperfusion injury, the <it>p57</it>^{<it>Kip</it>2}overexpressing hearts demonstrated preserved cardiac function compared to control mice with higher left ventricular developed pressure (63 ± 15 vs 30 ± 6 mmHg, p = 0.05), rate pressure product (22.8 ± 4.86 vs 10.4 ± 2.1 × 10³bpm × mmHg, p < 0.05) and coronary flow (3.5 ± 0.5 vs 2.38 ± 0.24 ml/min, p <0.05).</p> <p>Conclusion</p> <p>These data suggest that forced cardiac expression of p57^Kip2does not affect myocardial growth, differentiation and baseline function but attenuates injury from ischemia-reperfusion in the adult mouse heart.</p

Fog2 is required for normal diaphragm and lung development in mice and humans

Congenital diaphragmatic hernia and other congenital diaphragmatic defects are associated with significant mortality and morbidity in neonates; however, the molecular basis of these developmental anomalies is unknown. In an analysis of E18.5 embryos derived from mice treated with N-ethyl-N-nitrosourea, we identified a mutation that causes pulmonary hypoplasia and abnormal diaphragmatic development. Fog2 (Zfpm2) maps within the recombinant interval carrying the N-ethyl-N-nitrosourea-induced mutation, and DNA sequencing of Fog2 identified a mutation in a splice donor site that generates an abnormal transcript encoding a truncated protein. Human autopsy cases with diaphragmatic defect and pulmonary hypoplasia were evaluated for mutations in FOG2. Sequence analysis revealed a de novo mutation resulting in a premature stop codon in a child who died on the first day of life secondary to severe bilateral pulmonary hypoplasia and an abnormally muscularized diaphragm. Using a phenotype-driven approach, we have established that Fog2 is required for normal diaphragm and lung development, a role that has not been previously appreciated. FOG2 is the first gene implicated in the pathogenesis of nonsyndromic human congenital diaphragmatic defects, and its necessity for pulmonary development validates the hypothesis that neonates with congenital diaphragmatic hernia may also have primary pulmonary developmental abnormalities

Databases for Congenital Heart Defect Public Health Studies Across the Lifespan

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139106/1/jah31841_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139106/2/jah31841.pd

LEFT INTRAVENTRICULAR BALLOON PUMP ORTIMIZATION DURING INTRACTABLE CARDIAC ARREST

Η ΑΡΙΣΤΕΡΗ ΕΝΔΟΚΟΙΛΙΑΚΗ ΑΝΤΛΙΑ ΔΙ'ΑΕΡΟΘΑΛΑΜΟΥ ΕΙΝΑΙ ΜΙΑ ΜΕΘΟΔΟΣ ΤΑΧΕΙΑΣ ΕΦΑΡΜΟΓΗΣ ΠΟΥ ΜΠΟΡΕΙ ΝΑ ΔΙΑΤΗΡΗΣΕΙ ΙΚΑΝΟΠΟΙΗΤΙΚΗ ΚΑΡΔΙΑΚΗ ΠΑΡΟΧΗ ΕΠΙ ΠΕΙΡΑΜΑΤΟΖΩΩΝΜΕ ΠΑΥΣΗ ΤΗΣ ΚΑΡΔΙΑΚΗΣ ΛΕΙΤΟΥΡΓΙΑΣ ΤΟΥΣ.ΣΤΗΝ ΠΑΡΟΥΣΑ ΠΕΙΡΑΜΑΤΙΚΗ ΜΕΛΕΤΗ ΕΞΕΤΑΖΕΤΑΙ Η ΔΥΝΑΤΟΤΗΤΑ ΒΕΛΤΙΣΤΟΠΟΙΗΣΗ ΤΗΣ ΑΠΟΔΟΣΗΣ ΤΗΣ ΜΕ ΕΠΙΛΟΓΗ ΤΩΝ ΚΑΤΑΛΛΗΛΟΤΕΡΩΝ ΦΥΣΙΚΩΝ ΧΑΡΑΚΤΗΡΙΣΤΙΚΩΝ ΤΟΥ ΧΡΗΣΙΜΟΠΟΙΟΥΜΕΝΟΥ ΑΕΡΟΘΑΛΑΜΟΥ.ΕΙΔΙΚΟΤΕΡΑ,ΕΞΕΤΑΖΕΤΑΙ Η ΑΙΜΟΔΥΝΑΜΙΚΗ ΕΠΙΔΡΑΣΗ ΔΙΑΦΟΡΟΥ ΟΓΚΟΥ ΚΑΙ ΣΧΗΜΑΤΟΣ ΑΕΡΟΘΑΛΑΜΩΝ ΕΠΙ ΠΕΙΡΑΜΑΤΟΖΩΩΝ ΕΥΡΙΣΚΟΜΕΝΩΝ ΣΕ ΚΟΙΛΙΑΚΗ ΜΑΡΜΑΡΥΓΗ.ΣΕ 12 ΑΝΑΙΣΘΗΤΟΠΟΙΗΜΕΝΑ ΠΕΙΡΑΜΑΤΟΖΩΑ ΚΑΘΟΡΙΖΕΤΑΙ ΥΠΕΡΗΧΟΓΡΑΦΙΚΑ Ο ΤΕΛΟΔΙΑΣΤΟΛΙΚΟΣ ΟΓΚΟΣ ΤΗΣ ΑΡΙΣΤΕΡΑΣ ΚΟΙΛΙΑΣ(ΤΔΟΑΚ).ΕΝ ΣΥΝΕΧΕΙΑ,ΠΡΟΚΑΛΕΙΤΑΙ ΚΟΙΛΙΑΚΗ ΜΑΡΜΑΡΥΓΗ ΚΑΙ ΕΙΣΑΓΕΤΑΙ ΔΙΑ ΤΗΣΚΟΡΥΦΗΣ ΤΗΣ ΑΡΙΣΤΕΡΑΣ ΚΟΙΛΙΑΣ,ΜΕ ΤΗ ΒΟΗΘΕΙΑ ΕΙΣΑΓΩΓΕΩΣ, ΑΕΡΟΘΑΛΑΜΟΣ ΑΠΙΟΕΙΔΟΥΣ ΣΧΗΜΑΤΟΣ,ΤΟΥ ΟΠΟΙΟΥ Ο ΟΓΚΟΣ ΜΠΟΡΕΙ ΝΑ ΜΕΤΑΒΑΛΛΕΤΑΙ ΕΝΤΟΣ ΟΡΙΣΜΕΝΩΝ ΟΡΙΩΝ.ΔΟΚΙΜΑΖΟΝΤΑΙ ΤΡΕΙΣ ΔΙΑΦΟΡΕΤΙΚΟΙ ΟΓΚΟΙ ΠΡΙΜΟΔΟΤΗΣΕΩΣ ΤΟΥ ΑΕΡΟΘΑΛΑΜΟ:10ΚΑΤΑ 25% ΜΙΚΡΟΤΕΡΟΣ 2)ΚΑΤΑ 25% ΜΕΓΑΛΥΤΕΡΟΣ ΚΑΙ 3) ΙΣΟΣ ΜΕ ΤΟΝ ΤΔΟΑΚ ΚΑΙ ΣΥΓΚΡΙΝΕΤΑΙ Η ΑΠΟΔΟΣΗ ΤΟΥΣ.(ΑΠΟΚΟΠΗ ΠΕΡΙΛΗΨΗΣ)THE LEFT INTRAVENTRICULAR BALLON PUMP HAS BEEN PROVED AN EFFECTIVE METHOD OF MECHANICAL CIRCULATORY SUPPORT,WHEN IT WAS USED IN EXPERIMENTAL SETTING ON DOGS WITH CARDIAC ARREST.ITS PERFORMANCE,THOUGH,CAN BE OPTIMIZED BY IMPROVING THE FEATURES OF THE CATHETER-MOUNTED BALLON.THIS EXPERIMENTAL WORK EXPLORES THE HEMODYNAMIC EFFECT OF INTRAVENTRICULAR BALLON PUMPING DURING VENTRICULAR FIBRILATION,WITH BALLONS DIFFERING IN SHAPE AND VOLUME.THE LEFT VENTRICULAR AND DIASTOLIC VOLUME(LVEDV)WAS DETERMINED (BY MEANS OF 2D ECHO)IN 12 ANESTHETIZED DOGS AND VENTRICULAR FILBRILATION WAS INDUCED BY DIRECT CURRENT APPLICATION.A CATHETER-MOUNTED BALLON WAS INSERTED INTO THE LEFT VENTRICLE THROUGH AN INTRODUCER PLACED AT THE CARDIAC APEX.BALLON PUMPING WITH A FIXED RATE OF 75 CYCLES/MIN WAS INITIATED.THE PRIMING VOLUME COULD RANGE WITHIN CERTAIN LIMITS(LVEDV+-25%).BALLON PRIMED WITH VOLUME EQUAL TO THE LVEDV MAINTAINED THE HIGHEST MEAN SYSTOLIC AORTIC PRESSURE AND AORTIC FLOW(106,4+-2,7 MMHG AND 84,7+-2.35 ML/KG/MIN RESPECTIVELY)COMPARED TO THE SMALLER BY 25% OR THE LARGER BY 25% BALLON(P =0,002).FIVE DIFFERENT BALLON SHAPES(AT LEAST TWO IN EVERY DOG)WERE SUBSEQUENTLY IN 12 ANESTHETIZED DOGS WITH VENTRICULAR FIBRILATION :1)SPHERICAL 2)PEAR-SHAPED BALLON WITH THE GATHETER RUNNING THROUGH THE BALLON3)WITH A SHAPE BEING THE CAST OF THE LEFT VENTRICLE 4)BICONVEX-SHAPED BALLON 5)PEAR-SHAPED BALLON MOUNTED AT THE DISTAL TIP OF TTHE GATHETER.(ΑΠΟΚΟΠΗ ΠΕΡΙΛΗΨΗΣ

Surgical Placement Of Permanent Epicardial Pacing Systems In Very Low-Birth Weight Premature Neonates: A Review Of Data From The Pediatric Cardiac Care Consortium (Pccc)

This paper advances the state of the art for a computer-assisted approach to music generation called functional scaffolding for musical composition (FSMC), whose representation facilitates creative combination, exploration, and transformation of musical concepts. Music in FSMC is represented as a functional relationship between an existing human composition, or scaffold, and a generated accompaniment. This relationship is encoded by a type of artificial neural network called a compositional pattern producing network (CPPN). A human user without any musical expertise can then explore how accompaniment should relate to the scaffold through an interactive evolutionary process akin to animal breeding. While the power of such a functional representation has previously been shown to constrain the search to plausible accompaniments, this study goes further by showing that the user can tailor complete multipart arrangements from only a single original monophonic track provided by the user, thus enabling creativity without the need for musical expertise

The Role of Neural Crest during Cardiac Development in a Mouse Model of DiGeorge Syndrome

The velo-cardio-facial syndrome (VCFS)/DiGeorge syndrome (DGS) is a genetic disorder characterized by phenotypic abnormalities of the derivatives of the pharyngeal arches, including cardiac outflow tract defects. Neural crest cells play a major role in the development of the pharyngeal arches, and defects in these cells are likely responsible for the syndrome. Most patients are hemizygous for a 1.5- to 3.0-Mb region of 22q11, that is suspected to be critical for normal pharyngeal arch development. Mice hemizygous for a 1.5-Mb homologous region of chromosome 16 (Lgdel/+) exhibit conotruncal cardiac defects similar to those seen in affected VCFS/DGS patients. To investigate the role of Lgdel genes in neural crest development, we fate mapped neural crest cells in Lgdel/+ mice and we performed hemizygous neural crest-specific inactivation of Lgdel. Hemizygosity of the Lgdel region does not eliminate cardiac neural crest migration to the forming aortic arches. However, neural crest cells do not differentiate appropriately into smooth muscle in both fourth and sixth aortic arches and the affected aortic arch segments develop abnormally. Tissue-specific hemizygous inactivation of Lgdel genes in neural crest results in normal cardiovascular development. Based on our studies, we propose that Lgdel genes are required for the expression of soluble signals that regulate neural crest cell differentiation