A non-obese boy with Prader-Willi syndrome shows cardiopulmonary impairment due to severe kyphoscoliosis.
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Adolescent↗
Biomedical subjects
Takahiro Ishiwata
Publications and source records attributed to Takahiro Ishiwata.
GATA4 is a dosage-sensitive regulator of cardiac morphogenesis.
Normal heart development is orchestrated by a set of highly conserved transcription factors that includes GATA4, Nkx2-5, and Tbx5. Heterozygous mutation of each of these genes causes congenital heart disease in humans. In mouse models, haploinsufficiency for Nkx2-5 or Tbx5 resulted in an increased incidence of structural heart disease, confirming that normal heart development is sensitive to small changes in expression levels of Nkx2-5 and Tbx5. However, mice haploinsufficient for GATA4 have not been reported to have cardiac abnormalities. We generated two new GATA4 alleles, GATA4(H) and GATA4(flox). GATA4(flox/flox) embryos expressed 50% less GATA4 protein in the heart and survived normally. In contrast, GATA4(H/H) embryos expressed 70% less GATA4 protein in the heart and died between days 13.5 and 16.5 of gestation. These embryos had common atrioventricular canal (CAVC), double outlet right ventricle (DORV), hypoplastic ventricular myocardium, and normal coronary vasculature. Myocardial hypoplasia was associated with diminished cardiomyocyte proliferation. Hemodynamic measurements demonstrated that these embryos had normal systolic function, severe diastolic dysfunction, and atrioventricular regurgitation. Surprisingly, expression levels of the putative GATA4 target genes ANF, BNP, MEF2C, Nkx2-5, cyclin D2, and BMP4 were unchanged in mutant hearts, suggesting that GATA4 is not a dose-limiting regulator of the expression of these genes during later stages of embryonic cardiac development. These data demonstrate that multiple aspects of embryonic cardiac morphogenesis and function are exquisitely sensitive to small changes in GATA4 expression levels.
Animals↗
Developmental changes in ventricular diastolic function correlate with changes in ventricular myoarchitecture in normal mouse embryos.
Both genetic and epigenetic factors, such as abnormal hemodynamics, affect cardiac morphogenesis and the pathogenesis of congenital heart disease. Diastolic function is an important determinant of cardiac function, and tools for evaluating diastolic function in the embryo would be very valuable for assessment of cardiac performance. Using histological measurements of ventricular myoarchitecture, Doppler assessment of ventricular inflow velocities, and direct measurement of ventricular pressure, we investigated developmental changes of ventricular diastolic function in the mouse embryos from embryonic days 9.5 to 19.5. Regression analysis showed that peak velocity of A wave (an index of passive compliance) correlated with the area of trabecular myocardium in right ventricle (RV) (r2=0.92, P<0.0001) and left ventricle (LV) (r2=0.93, P<0.0001). Peak velocity of E wave (an index of active relaxation) exponentially correlated with the area of compact myocardium in RV (r2=0.98, P<0.0001) and LV (r2=0.97, P<0.0001). We used these techniques to analyze FOG-2 null embryos. FOG-2 null embryos had thin compact myocardium, higher EDP and E/A ratio, smaller -dP/dt, and diminished sucking pressure than wild-type littermates, indicating that decreased ventricular diastolic function might be the primary cause of embryonic lethality. In conclusion, during embryogenesis the development of compact myocardium tightly regulates the development of ventricular distensibility. Our study in normal mice forms the basis for future studies of embryonic cardiac function in genetically manipulated mice with abnormalities of the cardiovascular system.
Animals↗
Csm, a cardiac-specific isoform of the RNA helicase Mov10l1, is regulated by Nkx2.5 in embryonic heart.
Nkx2.5 (also called Csx) is an evolutionarily conserved cardiac transcription factor of the homeobox gene family. Nkx2.5 is required for early heart development, because Nkx2.5 null mice die before completion of cardiac looping. To identify genes regulated by Nkx2.5 in the developing heart, we performed differential screening in combination with suppression subtractive hybridization using RNA isolated from wild-type and Nkx2.5 null hearts at embryonic day 8.5. One gene that we found to be markedly down-regulated in the hearts from Nkx2.5 null embryos is an isoform of Mov10 like-1 (Mov10l1), a putative RNA helicase expressed in testis. We named this novel isoform as Csm (cardiac-specific isoform of Mov10l1). Csm is identical with the 3' region of the Mov10l1 gene, but its transcript starts from the exon 16 of Mov10l1. The conceptual protein encoded by Csm cDNA contains a helicase motif as well as ATPase and RNA interaction motifs. Csm is expressed specifically in the heart, and its expression in the heart is restricted to cardiac myocytes. Csm potentiated phenylephrine-induced hypertrophic response in cardiac myocytes. Furthermore, transient cotransfection analysis showed that Nkx2.5 transactivates the Csm promoter, suggesting that Nkx2.5 is essential for embryonic Csm expression.
Amino Acid Sequence↗
Myocardin expression is regulated by Nkx2.5, and its function is required for cardiomyogenesis.
Nkx2.5 (also known as Csx) is an evolutionarily conserved cardiac transcription factor of the homeobox gene family. Nkx2.5 is required for early heart development, since Nkx2.5-null mice die before completion of cardiac looping. To identify genes regulated by Nkx2.5 in the developing heart, we performed subtractive hybridization by using RNA isolated from wild-type and Nkx2.5-null hearts at embryonic day 8.5. We isolated a mouse cDNA encoding myocardin A, which is an alternative spliced isoform of myocardin and the most abundant isoform in the heart from embryo to adult. The expression of myocardin A and myocardin was markedly downregulated in Nkx2.5-null mouse hearts. Transient-cotransfection analysis showed that Nkx2.5 transactivates the myocardin promoter. Inhibition of myocardin function in the teratocarcinoma cell line P19CL6 prevented differentiation into cardiac myocytes after dimethyl sulfoxide treatment. Myocardin A transactivated the promoter of the atrial natriuretic factor gene through the serum response element, which was augmented by bone morphogenetic protein 2 and transforming growth factor beta-activated kinase 1. These results suggest that myocardin expression is regulated by Nkx2.5 and that its function is required for cardiomyogenesis.
Alternative Splicing↗
Nonobstructive ASD creation to qualify patients for the Fontan operation: effects on pulmonary hypertension due to restrictive left atrioventricular valve and interatrial communication.
Pulmonary hypertension (PH) due to elevated left atrial pressure (LAp) caused by restrictive left atrioventricular valve and interatrial communication sometimes precludes patients with univentricular heart from undergoing the Fontan operation. We have created atrial septal defect (ASD) for such patients to reduce LAp and then pulmonary arterial pressure (PAp) and pulmonary vascular resistance (Rp) in an attempt to qualify the patients for the Fontan repair. This study was performed to clarify the efficacy and limitation of this approach. Twelve patients with PH (mean PAp > 20 mm Hg and/or Rp > 3.0 Wood's unit/m(2)) due to obstruction at the LA exit underwent ASD creation at the age of 4.0 +/- 4.0 (mean +/- SD) years. Follow-up catheterization 14.9 +/- 15.6 months after the ASD creation demonstrated marked reductions in mean LAp (from 21 +/- 5 to 8 +/- 2 mm Hg), mean PAp (from 39 +/- 13 to 17 +/- 4 mm Hg), and Rp (from 6.2 +/- 4.5 to 2.7 +/- 1.4 Wood's unit/m(2)) compared with those before the procedure (all P < 0.0001). Seven of the 12 patients (58%) qualified for the Fontan operation (mean PAp < 20 mm Hg, Rp < 3.0 Wood's unit/m(2), and Nakata's PA index > or = 250) after the ASD creation. Final surgical outcomes of the seven patients included successful Fontan operation in five and biventricular repair in two. Patients with severe PH [mean PAp > or = 45 mm Hg (n = 6) or Rp > or = 4.5 Wood's unit/m(2) (n = 5)] before the ASD creation qualified less frequently for the Fontan repair than those with mild PH [mean PAp < 45 mm Hg (n = 6; 17% vs. 100%; P = 0.008) or Rp < 4.5 Wood's unit/m(2) (n = 7; 20 vs. 86%; P = 0.045)]. Patients with PA banded after 6 months of age (n = 3) qualified less frequently for the Fontan operation than those banded before 6 months of age (n = 6; 0 vs. 83%; P = 0.048). These data suggest that ASD creation is an effective approach to qualify patients for the Fontan operation in the presence of restrictive left atrioventricular valve and interatrial obstruction, except those with longstanding severe PH following delayed PA banding.
Cardiac Catheterization↗