Institut de recherches cliniques de Montréal (IRCM) 110, avenue des Pins ouest Montréal (Québec) Canada H2W 1R7 September 25, 2009 63rd High Blood Pressure Conference 2009 Lewis K. Dahl Memorial Lecture Cardioprotective effects of cyclic GMP: lessons from animal genetic models Affiliated to Université de Montréal No relationship to disclose
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Institut de recherches cliniques de Montréal (IRCM)110, avenue des Pins ouestMontréal (Québec) CanadaH2W 1R7
September 25, 200963rd High Blood Pressure Conference 2009Lewis K. Dahl Memorial Lecture
Cardioprotective effects of cyclic GMP: lessons from animal genetic models
Affiliated to Université de Montréal
No relationship to disclose
Lewis K. Dahl: Web visibility…
Cardioprotective effects of cyclic GMP: lessons from animal genetic models
Lewis K. Dahl: Web visibility…
Lewis K. Dahl: enduring contributions
Cardioprotective effects of cyclic GMP: lessons from animal genetic models
Comparison of hypertension among geographically distinct populations with different salt intake levels• review published in:
• reprinted in: Int. J. Epidemiol. 34: 967–972 (2005)
Demonstration of the role of genetic factors in susceptibility to experimental hypertension due to chronic excess salt
• Nature 194: 480-482 (1962)• J. Exp. Med. 115: 1173-1190 (1962)• discussed in recent editorial: J. Exp. Med. 204: 1507 (2007)
Selective breeding program to establish genetic experimental models of salt-sensitive hypertension
• New rat strains: Dahl-S and Dahl-R• further established into inbred rat strains by J.R. Rapp• used in numerous animal genetic studies
Novel inbred rat strains: WKHT and WKHA
Cardioprotective effects of cyclic GMP: lessons from animal genetic models
XWKY SHR
F1
F2
Syst. BP: ≡
WKY
Activity: > WKY, ≡
SHR
HW/BW: > WKY, < SHR
Phenotype selection followed by inbreeding
WKHA WKHT
Cross performed by E.D. Hendley (U. of Vermont)
Syst. BP: > WKY, ≡
SHR
Activity: ≡
WKY, < SHR
HW/BW: > WKY, < SHR
Note: WKHA are not “hyperactive”
Cardioprotective effects of cyclic GMP: lessons from animal genetic models
WKY
SHR
WKHA
LEWISWISTAR
0
200
400
600
800
1000
rat strain
Loco
mot
or a
ctiv
ity
⇒ one should be cautious not to define quantitative phenotypes as “normal” or “abnormal” in absolute terms, but only in comparison to other phenotypes within a species
WKHA have concentric LVH vs. WKY
Cardioprotective effects of cyclic GMP: lessons from animal genetic models
ANF in ventricles
Ventricular weight0
50
100
150
200
250
fmol
e / m
g w
et w
eigh
t
2.90
3.10
3.30
3.50
Ven
tr. w
eigh
t / b
ody
wei
ght
WKY WKHAAdditional observation: LV concentration of ANF correlates negatively with LV weight → → → →
F2 intercross between WKY and WKHA
Cardioprotective effects of cyclic GMP: lessons from animal genetic models
F2
F1 X X
P1 P2n
phenotype
n
phenotype
X
n
n
phenotype
phenotype
F2 GENETIC INTERCROSS
* *
*
*** variance = environment** variance = environment x genetics
F2
F1 X XF1 X X
P1 P2n
phenotype
n
phenotype
X
n
n
phenotype
phenotype
F2 GENETIC INTERCROSS
* *
*
*** variance = environment** variance = environment x genetics
Co-segregation analysis in F2 population
Cardioprotective effects of cyclic GMP: lessons from animal genetic models
L.V. weight / body weight tertile
lower mid higherlower mid higher40
60
80
100
120
fmol
e / m
g w
et w
eigh
t
ANF peptide
(31)
(72)
(41)
lower mid higher0.70
0.95
1.20
O.D
. rat
io
β-MHC mRNA
(30)
(23)
(24)
0.20
0.45
0.70
O.D
. rat
io
ANF mRNA
(18)
(45)
(25)
Circ. Res., 84:1453-1458 (1999)
Detection of QTLs for LVM and LV ANF
Cardioprotective effects of cyclic GMP: lessons from animal genetic models