genetic basis of thoracic aortic aneurysms and acute ...mutations decreasing smc contraction: htn...
Post on 04-Jun-2020
2 Views
Preview:
TRANSCRIPT
Genetic Basis of Thoracic Aortic AneurysmsGenetic Basis of Thoracic Aortic AneurysmsAnd Acute Aortic Dissections
Dianna M. Milewicz, M.D. Ph.D.University of Texas Health Science Center at Houston
McGovern Medical SchoolMcGovern Medical School
SyndromicFamilial
Genetic Risk for Thoracic Aortic Disease
Familial
SporadicSporadic
Genetic variants thatconfer a low risk
Rare variants withhigh risk,high risk,
“mutations”
FBN1 fibrillin-1
Heritable Thoracic Aortic Disease GenesHeritable Thoracic Aortic Disease Genes
FBN1 fibrillin-1MFAP5 microfibril associated protein 2LOX lysyl oxidase
TGFBR1 TGF-β receptor type I
ECM
TGFBR1 TGF-β receptor type ITGFBR2 TGF-β receptor type I SMAD3 Smad3TGF-β SMAD3 Smad3SMAD4 Smad4TGFB2 TGF-β2TGFB3 TGF-β3
TGF-βSignaling
TGFB3 TGF-β3SMAD2 Smad2
ACTA2 SM α-actinSMC
ACTA2 SM α-actinMYH11 SM myosin heavy chainMYLK myosin light chain kinasePRKG1 cGMP-dependent kinase I
SMCContraction
PRKG1 cGMP-dependent kinase I
MAT2A methionine adenosyltransferases IIαFOXE3 forkhead transcript factor E3
Medial Layer of the Aorta:Smooth Muscle Cells and ElastinSmooth Muscle Cells and Elastin
“Smooth Muscle Cell to Elastic Lamina Connections in Developing Mouse Aorta”, Davis. Elaine, 1993, Laboratory Investigation, 68 (1), p. 97
Mutations Decreasing SMC contraction:HTN
Mutations Decreasing SMC contraction:ACTA2, MYH11, MYLK, and PRKG1
HTN
SMC “mechnosensor” for aortic forcesthrough the elastin – contractile unitsthrough the elastin – contractile units
Activation of SMC cellular “repair” pathways:Activation of SMC cellular “repair” pathways:Angiotensin II and TGF-β signaling; increased MMPs and proteoglycans
Thoracic Aortic Aneurysm and Dissection
increased MMPs and proteoglycans
Thoracic Aortic Aneurysm and Dissection
Milewicz et al. Ann Rev Hum Gen Genomics, 2008
Humphrey, Milewicz, Schwartz and Tellides, Science 2014
SyndromicFamilial
Genetic Risk for Thoracic Aortic Disease
Familial
SporadicSporadic
Genetic variants thatconfer a low risk
Rare variants withhigh risk,high risk,
“mutations”
• 355 T ypeA and B dissectionscases;85% HT N• 355 T ypeA and B dissectionscases;85% HT N
• 9% had am utationinaHT AD gene
• 30% had ararevariantinaknow ngenebutnot• 30% had ararevariantinaknow ngenebutnotknow nm utation
• Highly significantincreased burdenw hen• Highly significantincreased burdenw hencom paredtocontrols(OR 2.775 (95% CI 2.08 -3.7); p= 9.0 x 10-11)3.7); p= 9.0 x 10-11)
• We hypothesize that these HTAD gene rarevariants predispose to dissections but require avariants predispose to dissections but require asecond hit.
D o My h 11R247 C M ic e GetThorac ic A ortic D iseasewith aS ec ond H it?
* * n=30
*P <0.05
P =0.03n=39 *
Type A dissection with
2Section 1 Section 2
aorta
Type A dissection withpericardial tamponade Type B dissections
1
aorta
C harac terization ofP ostnatalMy h 11R247C A ortas
W T My h 11R247C
C harac terization ofH TN W T and My h 11R247C A ortas
W T My h 11R247C
Hypertension activates pathways downstream of focal adhesions Hypertension activates pathways downstream of focal adhesions
Therapeutic Manipulation of Aortic DissectionRates in the Myh11R247C MiceRates in the Myh11R247C Mice
P =0.002
P =0.05
HT AD isagenetically heterogeneousHT AD isagenetically heterogeneouscondition
Com m onpathw ay todiseaseisalteredCom m onpathw ay todiseaseisalteredm echanosensingthroughtheelastin-m echanosensingthroughtheelastin-contractileunit.
S poradicdiseaseisduetoalow riskS poradicdiseaseisduetoalow riskvariantinapresdisposinggeneplusasecondhit.secondhit.
UTHSC at Houston (UTHealth)Dongchuan Guo, Ph.DEllen Regalado, M.S.
Baylor College of MedicineSuzanne Leal, Ph.D.Regie Santos-Cortez, Ph.D.Ellen Regalado, M.S.
Stephanie Wallace, M.S.Shanzhi Wang, Ph.D.Jiyuan Chen, Ph.D.Callie Kwartler, Ph.D.
Regie Santos-Cortez, Ph.D.Scott LeMaire, M.D.Joseph Coselli, M.D.Shaine Morris, M.D.
Callie Kwartler, Ph.D.Shuongtao Ma, Ph.D.Ginger Tsai, M.S.Siddharth Prakash, M.D. Ph.D.
University of WashingtonDeborah Nickerson, Ph.D.Michael Bamshad, M.D.Siddharth Prakash, M.D. Ph.D.
Zhen Zhou, Ph.D.Anthony L. Estrera, M.D.Hazim J. Safi, M.D.
Michael Bamshad, M.D..
Hazim J. Safi, M.D.
Yale UniversityJay D. Humphrey, Ph.D. GenTACJay D. Humphrey, Ph.D.George Tellides, M.DMartin A. Schwartz, Ph.D.
GenTAC
TGF-β Cellular Signaling:Loss of function mutations cause TAADLoss of function mutations cause TAAD
TGF-βTGF-β2/3
Smad3
My h 11R247 C A lters M yosin Fu nc tion:D oes NotC au se A ortic A neu rysm sD oes NotC au se A ortic A neu rysm s
De
ve
lop
ed
Fo
rce p<0.05
B ac u loviru s expression A ortic Ring C ontrac tion
1p<0.05
De
ve
lop
ed
Fo
rce
g/m
gti
ss
ue
My
os
ine
nzy
ma
tic
ac
tiv
ity
0.4
0.6
0.8
1
WT Myh11R247C
W T M yh11R247 C
De
ve
lop
ed
Fo
rce
g/m
gti
ss
ue
My
os
ine
nzy
ma
tic
ac
tiv
ity
0
0.2
W T M yh11R247 C
WT Myh11R247C
H&E
WT Myh11R247C
Elastin
top related