ras-cuing the heart (cardiology 2011)
TRANSCRIPT
Fraz Ahmed Ismat, MDClinical 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 typee13.5
Nf1 -/-
e13.5
Gitler, et al., Nat Gen 2003
Disease-causing mutations occur throughout NF1
… but only the NF1 GAP-Related Domain (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
Nf1+/+ 13 17 27
Nf1+/+, GRDk/+ 13 17 13
Nf1+/+, CMV-cre+ 13 17 15
Nf1+/+, GRDk/+, CMV-cre+ 13 17 17
Nf1+/- 26 35 22
Nf1+/-, GRDk/+ 26 35 40
Nf1+/-, CMV-cre+ 26 35 37
Nf1+/-, GRDk/+, CMV-cre+ 26 35 32
Nf1-/- 13 0 0
Nf1-/-, GRDk/+ 13 0 0
Nf1-/-, CMV-cre+ 13 0 0
Nf1-/-, GRDk/+, CMV-cre+ 13 0 5*
Genotype Mendelian Expected Observed
* All rescued Nf1-/- mice died on the first postpartum day.Ismat et al., JCI 2006
Late mortality in Nf1 myocardial knockout
n=23
n=20
Progressive cardiac hypertrophy & fibrosis in Nf1mKO
Cardiac dilation & reduced shortening in Nf1mKO
Rescue of Nf1mKO cardiac hypertrophy with NF1 GRD
Hypertrophic occlusive vasculopathy in NF1
Kanter et al., J Peds 2006
“Normal” arteries in Nf1 smooth muscle knock-out (Nf1smKO)
No anatomical differences seen in elastin (A, B) and smooth muscle α-actin staining (C, D)
between wild type and Nf1smKO arteries.
Xu & Ismat et al., Circ 2007
Elevated blood pressures in Nf1smKO mice
Junwang Xu & Tao Wang
Nf1smKO injury-induced intimal hyperplasia rescued by GRD
Xu & Ismat et al., Circ 2007
Tidyman & RauenCurrent Opinion in Genetics & Development2009, 19:230–236
(PTPN 1 1 )
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 LabAlmedia McCoyTimothy Macatee
MCRC Core FacilitiesHistology Core (MM Lu)Transgenic Core (D Zhu)Physiology Core (T Wang*)
Penn Core FacilitiesFlow Cytometry & Cell SortingSmall Animal ImagingMicroarray 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)