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Biomedical subjects

Rajan Wadhawan

Publications and source records attributed to Rajan Wadhawan.

5 recordsLinked to original sources
PubMed2005

Ontogeny of phosphoinositide 3-kinase signaling in developing heart: effect of acute beta-adrenergic stimulation.

Signaling pathways underlying transition of cardiomyocyte growth from hyperplasia in fetal/newborn to hypertrophy in postnatal/adult hearts are not well understood. We have shown that beta-adrenergic receptor (beta-AR)-mediated regulation of neonatal cardiomyocyte proliferation involves p70 ribosomal protein S6 kinase (p70S6K). Here we examined the ontogeny of phosphoinositide 3-kinase (PI3K)/p70S6K signaling pathway in rat hearts and investigated the influence of beta-AR on this pathway during development. Cardiac PI3K and p70S6K1 activities were high in the embryonic day 20 fetus, decreased gradually postnatally, and were low in the adult. In contrast, p70S6K2 was barely detectable. Phosphorylation of p70S6K1, Akt, and phosphoinositide-dependent protein kinase 1 were markedly increased in late gestation and early postnatal life but not in adult hearts. Phosphatase and tensin homolog on chromosome 10 (PTEN), a negative regulator of PI3K, was highly expressed in adult hearts but only at low levels and mostly in the phosphorylated (inactivated) form in the fetus. Beta-AR stimulation resulted in increased cardiac p70S6K1 activity only in animals > or = 2 wk old, whereas Akt level was increased in all developmental stages tested. These increases were accompanied by increased Bcl-2 associated death promoter (Ser136) phosphorylation without changes in PTEN level. Thus there is globally high input of cardiac PI3K signaling during the fetal-neonatal transition period. Inactivation of PTEN may in part contribute to the high activity of PI3K signaling, which coincides with the period of high cardiomyocyte proliferation. Beta-AR stimulation activates cardiac p70S6K1 and Akt in postnatal animals and may activate cardiac survival signals. These data provide further evidence for the importance of beta-AR and PI3K signaling in the regulation of cardiac growth during development.

Adrenergic beta-Agonists↗
PubMed2003

Does labor influence neonatal and neurodevelopmental outcomes of extremely-low-birth-weight infants who are born by cesarean delivery?

OBJECTIVE: The purpose of this study was to examine the influence of labor on extremely-low-birth-weight infants who were born by cesarean delivery with reference to neonatal and neurodevelopmental outcomes. We hypothesized that infants who are born by cesarean delivery without labor will have better outcomes than those infants who are born by cesarean delivery with labor. STUDY DESIGN: This was a retrospective cohort study of extremely-low-birth-weight infants (birth weight, 401-1000 g) who were born by cesarean delivery and cared for in the National Institute for Child Health and Human Development Neonatal Network, during calendar years 1995 to 1997. A total of 1606 extremely-low-birth-weight infants were born by cesarean delivery and survived to discharge. Of these, 1273 infants (80.8%) were examined in the network follow-up clinics at 18 to 22 months of corrected age and had a complete data set (667 infants were born without labor, 606 infants were born with labor). Outcome variables that were examined include intraventricular hemorrhage grade 3 to 4, periventricular leukomalacia, and neurodevelopmental impairment. RESULTS: Mothers in the cesarean delivery without labor group were older (P<.001), more likely to be married (P<.05), less likely to be supported by Medicaid (P<.01), more likely to have preeclampsia/hypertension (P<.001), more likely to receive prenatal steroids (P<.005), and less likely to have received antibiotics (P<.001). Infants who were born by cesarean delivery without labor had higher gestational age (P<.001), lower birth weight (P<.01), and were less likely to be outborn (P<.001). By univariate analysis, infants who were born by cesarean delivery with labor had a higher incidence of grade 3 to 4 intraventricular hemorrhage (23.3% vs 12.1%, P<.001), periventricular leukomalacia (8.5% vs 4.7%, P<.02), and neurodevelopmental impairment (41.7% vs 34.6%, P<.02). Logistic regression analysis that controlled for all maternal and neonatal demographic and clinical variables that were statistically associated with labor or no labor revealed that the significant differences in grade 3 to 4 intraventricular hemorrhage, periventricular leukomalacia, and neurodevelopmental impairment were no longer evident. CONCLUSION: In extremely-low-birth-weight infants who were born by cesarean delivery and after control for other risk factors, labor does not appear to play a significant role in adverse neonatal outcomes and neurodevelopmental impairment at 18 to 22 months of corrected age.

Adult↗
PubMed2003

Regulation of cardiac beta 1-adrenergic receptor transcription during the developmental transition.

The beta(1)-adrenergic receptor (beta(1)AR) gene contains binding sites for myc/max proteins within a glucocorticoid response element. Transcriptional activation of the beta(1)AR is the result of cooperative binding between c-myc and the glucocorticoid receptor on the beta(1)AR promoter. The transcriptional regulation of both beta(1)AR and c-myc are developmentally regulated. We used transcription rate assays of nuclei isolated from fetal hearts to demonstrate a fivefold increase in the transcription rate of beta(1)AR vs. postnatal hearts (P < 0.01). This was associated with a fourfold increase in c-myc transcription. Transcription rate assays performed in a rat fibroblast cell line that overexpresses c-myc (myc(+/+)) showed similarly increased beta(1)AR expression compared with the wild-type cell line. Transient transfection experiments in the myc(+/+) cells demonstrated robust expression of beta(1)AR promoter constructs, which was abrogated by mutation of the myc/max binding site or by cotransfection with a c-myc antisense expression vector. These results suggest that the regulation of cardiac beta(1)AR transcription and the expression of c-myc are tightly integrated.

Animals↗
PubMed2002

Molecular interactions between glucocorticoid and catecholamine signaling pathways.

To study the mechanism underlying glucocorticoid regulation of the beta(1)-adrenergic receptor (beta(1)AR), we identified a 43-bp region (-1274 to -1232 from the translation start site) that contains a novel glucocorticoid regulatory unit (GRU) that confers glucocorticoid responsiveness. The sequence encompassing the GRU is (5')TAATTA(3'), which is a core-binding motif for the homeodomain proteins; an E-box ((5')CACGTG(3')) binding site for the Myc/Max family proteins, and an overlapping glucocorticoid response element half-site ((5')TGTTCT(3')). We showed that the half-site is critical for GRU-protein interactions, which also require binding of proteins to the E-box and the homeodomain region. Expression of proteins binding to the GRU was shown to be developmentally regulated, being high in embryonic hearts, reduced in newborn hearts, and undetectable in adult hearts. Overexpression of c-myc antisense significantly reduced glucocorticoid responsiveness of the beta(1)AR gene. We further demonstrated that transcriptional regulation of the beta(1)AR gene is closely related to that of the c-myc gene and that the beta(1)AR may be a potential target of c-myc. We conclude that the ovine beta(1)AR gene contains a novel, functional GRU and that the nuclear factors that transactivate through this element may have important developmental implications.

Animals↗