Polygenic (essential) hypertension is a leading risk factor for heart disease, stroke and renal failure. Despite increasing efforts to decipher its etiology, the genetic determinants of susceptibility to hypertension and its target organ complications remain to be fully elucidated. We have recently performed a comparative total genome scan for QTLs (quantitative trait loci) underlying salt-sensitive hypertension and its associated target- organ complications (hypertensive renal disease and cardiac hypertrophy) in F2-intercross male and female populations derived from Dahl rats. We found that most QTLs detected across the three phenotypes were gender-specific supporting the hypothesis that there are distinct genetic determinants of hypertension susceptibility between genders. Furthermore, we note that our F2 female cohort represents a pre-menopausal model of salt-sensitive hypertension, fact that raises the question if similar or different loci might confer salt- sensitive hypertension susceptibility in post-menopausal females, issue that is particularly relevant since cardiovascular disease risk is known to increase in post-menopausal women. Thus, the proposed studies are aimed: a) to delimit further the genomic regions containing selected blood pressure (BP) QTLs in male and pre-menopausal females by the development of strategic congenic strains carrying specific chromosomal regions spanning the detected QTLs and b) to perform a genome scan for QTLs affecting BP, renal disease and relative heart weight in an F2 (R x S)-intercross female rat population in which salt-sensitive hypertension and target organ complications are induced after menopause (i.e.: high salt challenge began at 14 months of age). Comparison between pre-menopausal and post-menopausal genome scans will evaluate if similar or different chromosomal regions underlie BP and target organ damage susceptibility in females depending upon their menopausal status. Project Narrative: Hypertension is a leading risk factor for heart disease, stroke and renal failure. Despite increasing efforts to decipher the genetic determinants of susceptibility to hypertension and its target organ associated complications, the genetic underpinnings of hypertension remain to be fully elucidated. Our research will help to elucidate the genetic factors underlying susceptibility to hypertension and target-organ complications in males, pre- and post-menopausal females. This information will provide critical experimental support for the paradigmatic shift towards the independent investigation in males and females of mechanisms, intervention and prevention strategies for essential hypertension and its target organ complications.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL086532-04
Application #
8120701
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
OH, Youngsuk
Project Start
2008-09-01
Project End
2013-07-31
Budget Start
2011-08-01
Budget End
2013-07-31
Support Year
4
Fiscal Year
2011
Total Cost
$406,250
Indirect Cost
Name
Boston University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Herrera, Victoria L; Pasion, Khristine A; Tan, Glaiza A et al. (2013) Dahl (S × R) rat congenic strain analysis confirms and defines a chromosome 17 spatial navigation quantitative trait locus to <10 Mbp. PLoS One 8:e58280
Herrera, Victoria L; Pasion, Khristine A; Tan, Glaiza A et al. (2013) Sex-specific effects on spatial learning and memory, and sex-independent effects on blood pressure of a <3.3 Mbp rat chromosome 2 QTL region in Dahl salt-sensitive rats. PLoS One 8:e67673
Herrera, Victoria L M; Pasion, Khristine A; Moran, Ann Marie et al. (2013) Worse renal disease in postmenopausal F2[Dahl S x R]-intercross rats: detection of novel QTLs affecting hypertensive kidney disease. PLoS One 8:e56096
Herrera, Victoria L; Matsubara, Yuichi; Ponce, Lorenz R et al. (2012) Distinct QTLs cosegregate with worse hypertension and renal disease in ovariectomized F2[Dahl S ýý R]-intercross rats. J Hypertens 30:1572-80
Herrera, Victoria L M; Pasion, Khristine A; Moran, Ann Marie et al. (2012) Dahl (S x R) congenic strain analysis confirms and defines a chromosome 5 female-specific blood pressure quantitative trait locus to <7 Mbp. PLoS One 7:e42214
Herrera, Victoria L M; Pasion, Khristine A; Moran, Ann Marie et al. (2012) Differential genetic basis for pre-menopausal and post-menopausal salt-sensitive hypertension. PLoS One 7:e43160
Herrera, Victoria L M; Bagamasbad, Pia; Decano, Julius L et al. (2011) AVR/NAVR deficiency lowers blood pressure and differentially affects urinary concentrating ability, cognition, and anxiety-like behavior in male and female mice. Physiol Genomics 43:32-42
Herrera, Victoria L M; Decano, Julius L; Steffen, Martin et al. (2009) Autophagy: insights from DEspR-deficiency and haploinsufficiency. Autophagy 5:259-62