Ras-cuing the Heart (Cardiology 2011)
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Ras-cuing the Heart (Cardiology 2011)



Presented at Cardiology 2011, 15th Annual Update on Pediatric and Congenital Cardiovascular Disease.

Presented at Cardiology 2011, 15th Annual Update on Pediatric and Congenital Cardiovascular Disease.



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  • The mouse model of Neurofibromatosis, in which the disease gene, Nf1, has been “knocked-out”, demonstrates embryonically lethal cardiovascular defects in the homozygous mutant state. They die in mid-gestation from a series of cardiovascular defects, arising in large part from defects involving endothelial tissues. The cardiovascular failure, demonstrated by the large pericardial effusion in panel B (*), is a manifestation of this series of defects. Most notable from among these abnormalities are enlarged endocardial cushions resulting from abnormal endothelial to mesenchymal transformation, (dashed line, panel B), ventricular septal defects (arrows, panel D) and malrotation of the cardiac outflow tract, and a thinned, non-compacted ventricular myocardium (arrowheads, panel F).
  • NF1 encodes neurofibromin, a large protein expressed ubiquitously throughout development. The bulk of neurofibromin is of unknown function, but a small domain, known as the GAP-related domain (or GRD) shares homology with several Ras-GTPase activating proteins, or GAPs. GAPs downregulate the activity of Ras protooncogenes.

Ras-cuing the Heart (Cardiology 2011) Ras-cuing the Heart (Cardiology 2011) Presentation Transcript

    • Fraz Ahmed Ismat, MD
    • Clinical Associate in Pediatrics, Division of Cardiology
    • The Children’s Hospital of Philadelphia
    Ras -cuing the Heart Nf1 in Cardiovascular Development & Disease
  • Nf1 -/- embryos die of cardiovascular failure Jacks T. et al., Nat Gen 1994
  • Nf1 -/- hearts have a lethal series of defects wild type e13.5 Nf1 -/- e13.5 Gitler, et al., Nat Gen 2003
  • Disease-causing mutations occur throughout NF1 … but only the NF1 G AP- R elated D omain (GRD) has a well-described function
  • NF1 GRD downregulates activated Ras Ismat et al., JCI 2006
  • GRD expression rescues Nf1 -/- embryonic heart defects NF1 GRD expression rescues pericardial effusion ( ), enlarged endocardial cushion ( arrows ), and myocardial thinning (arrowheads). * Ismat et al., JCI 2006
  • GRD rescued Nf1 -/- mice die soon after birth Genotype Mendelian Expected Observed * All rescued Nf1 -/- mice died on the first postpartum day. Ismat et al., JCI 2006 Nf1 +/+ 13 17 27 Nf1 +/+ , GRD k/+ 13 17 13 Nf1 +/+ , CMV-cre + 13 17 15 Nf1 +/+ , GRD k/+ , CMV-cre + 13 17 17 Nf1 +/- 26 35 22 Nf1 +/- , GRD k/+ 26 35 40 Nf1 +/- , CMV-cre + 26 35 37 Nf1 +/- , GRD k/+ , CMV-cre + 26 35 32 Nf1 -/- 13 0 0 Nf1 -/- , GRD k/+ 13 0 0 Nf1 -/- , CMV-cre + 13 0 0 Nf1 -/- , GRD k/+ , CMV-cre + 13 0 5*
  • Late mortality in Nf1 myocardial knockout n=23 n=20
  • Progressive cardiac hypertrophy & fibrosis in Nf1 mKO
  • Cardiac dilation & reduced shortening in Nf1 mKO
  • Rescue of Nf1 mKO cardiac hypertrophy with NF1 GRD
  • Hypertrophic occlusive vasculopathy in NF1 Kanter et al., J Peds 2006
  • “ Normal” arteries in Nf1 smooth muscle knock-out ( Nf1 smKO) No anatomical differences seen in elastin ( A , B ) and smooth muscle α - actin staining ( C , D ) between wild type and Nf1 smKO arteries. Xu & Ismat et al., Circ 2007
  • Elevated blood pressures in Nf1 smKO mice Junwang Xu & Tao Wang
  • Nf1 smKO injury-induced intimal hyperplasia rescued by GRD Xu & Ismat et al., Circ 2007
  • Tidyman & Rauen Current Opinion in Genetics & Development 2009, 19:230–236 (PTPN11)
  • Acknowledgements Past support: a Young Investigator Award from the Children’s Tumor Foundation , a Physician Scientist Development Award (K08) from the NHLBI ; Current support: a Basil O’Connor scholarship from the March of Dimes Foundation , a cardiovascular research grant from the W.W. Smith Charitable Trust , and grants from the CHOP Cardiac Center Scientific Review Committee . Ismat Lab Almedia McCoy Timothy Macatee MCRC Core Facilities Histology Core (MM Lu) Transgenic Core (D Zhu) Physiology Core (T Wang*) Penn Core Facilities Flow Cytometry & Cell Sorting Small Animal Imaging Microarray Core Facility Collaborators & Others Jonathan Epstein (Penn) Aaron Gitler (Penn) Elizabeth Goldmuntz (CHOP) Tyler Jacks (MIT) Maria Kontardis (BIDH-HMS) Thomas Look (DFCI) Arun Padmanabhan (Penn) Luis Parada (UTSW) Nancy Ratner (Cincinnati) Xin Zhang (IUPUI) Yuan Zhu (Michigan)