© 1999 American Heart Association, Inc.
Molecular Medicine |
Altered Structure, Regulation, and Function of the Gene Encoding the Atrial Natriuretic Peptide in the Stroke-Prone Spontaneously Hypertensive Rat
From the Division of Cardiovascular Diseases (S.R., M.A.L.-K., B.G., K.L.), Department of Medicine, Brigham and Women’s Hospital, and the Department of Cardiology (K.L.), Children’s Hospital, Harvard Medical School, Boston, Mass; Istituto Neurologico Mediterraneo Neuromed, Pozzilli (S.R., P.D., R.G., A.L., M.V.), and the Department of Experimental Medicine and Pathology, La Sapienza University (M.V., S.R.), Rome, Italy; and the Max Delbruch Centre for Molecular Medicine (K.L.), Berlin, Germany. Dr Lee-Kirsch is currently affiliated with the Universitaetskinderklinik, Technische Universittaet t Dresden, Dresden, Germany.
Correspondence to Speranza Rubattu, MD, Istituto Neurologico Mediterraneo Neuromed (Parco Tecnologico), Localita Camerelle (Zona Industriale). 86077 Pozzilli (Is), Italy. E-mail rubattu.speranza{at}neuromed.it
Abstract—Through the
genotype/phenotype cosegregation analysis of an
F2 intercross, from the crossbreeding of stroke-prone
spontaneously hypertensive rats (SHRSP) and stroke-resistant
spontaneously hypertensive rats (SHR), we previously identified a
quantitative trait locus for stroke on rat chromosome 5
(STR2) that colocalized with the genes encoding atrial
and brain natriuretic peptides (ANP and
BNP) and conferred a stroke-delaying effect. To further
characterize ANP and BNP as candidates
for stroke, we performed additional studies. Comparative sequence
analysis revealed point mutations in both the coding and
regulatory regions of ANP, whereas no interstrain
differences were found for BNP. In in vitro studies in
COS-7 and AtT-20 cells that were performed to test the relevance of a
G
A substitution at position 1125, a GlySer transposition
in the SHRSP pro-ANP peptide resulted in different posttranslational
processing of the SHRSP ANP gene product that was also associated
with higher cGMP production (P<0.05).
Furthermore, an analysis of a 5' end mutation affecting a PEA2
regulatory binding site in the 5' untranslated regulatory
sequence of SHRSP ANP demonstrated a significantly lower
ANP promoter activation in endothelial
cells (P<0.05 versus the SHR ANP). In addition, the
expression of ANP was significantly reduced in the
brain, but not in the atria, of SHRSP compared with SHR
(P<0.0001). No differences were detected with regard to
BNP expression. The present results reveal
substantial differences in ANP, but not
BNP, structure and product among SHR and SHRSP,
which supports a role of ANP in the pathogenesis of
stroke in the SHRSP animal model.
Key Words: genetics • atrial natriuretic peptide • stroke • natriuretic peptide
This article has been cited by other articles:
 |
|
 |
|
  P. De Paolis, V. Nobili, A. Lombardi, D. Tarasi, D. Barbato, S. Marchitti, U. Ganten, E. Brunetti, M. Volpe, and S. Rubattu Role of a Molecular Variant of Rat Atrial Natriuretic Peptide Gene in Vascular Remodeling Ann. Clin. Lab. Sci., January 1, 2007; 37(2): 135 - 140. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Rubattu, N. Hubner, U. Ganten, A. Evangelista, R. Stanzione, E. D. Angelantonio, R. Plehm, R. Langanki, E. Gianazza, L. Sironi, et al. Reciprocal congenic lines for a major stroke QTL on rat chromosome 1 Physiol Genomics, October 11, 2006; 27(2): 108 - 113. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. A. Babiker, D. Lips, R. Meyer, E. Delvaux, P. Zandberg, B. Janssen, G. van Eys, C. Grohe, and P. A. Doevendans Estrogen Receptor {beta} Protects the Murine Heart Against Left Ventricular Hypertrophy Arterioscler Thromb Vasc Biol, July 1, 2006; 26(7): 1524 - 1530. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Rubattu, R. Stanzione, E. Di Angelantonio, B. Zanda, A. Evangelista, D. Tarasi, B. Gigante, A. Pirisi, E. Brunetti, and M. Volpe Atrial Natriuretic Peptide Gene Polymorphisms and Risk of Ischemic Stroke in Humans Stroke, April 1, 2004; 35(4): 814 - 818. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. J. Wang, M. G. Larson, D. Levy, E. J. Benjamin, E. P. Leip, T. Omland, P. A. Wolf, and R. S. Vasan Plasma Natriuretic Peptide Levels and the Risk of Cardiovascular Events and Death N. Engl. J. Med., February 12, 2004; 350(7): 655 - 663. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Fornage, M. W. Swank, E. Boerwinkle, and P. A. Doris Gene expression profiling and functional proteomic analysis reveal perturbed kinase-mediated signaling in genetic stroke susceptibility Physiol Genomics, September 29, 2003; 15(1): 75 - 83. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Pravenec, C. Wallace, T. J. Aitman, and T. W. Kurtz Gene Expression Profiling in Hypertension Research: A Critical Perspective Hypertension, January 1, 2003; 41(1): 3 - 8. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. F. Deschepper, I. Boutin-Ganache, A. Zahabi, and Z. Jiang In Search of Cardiovascular Candidate Genes: Interactions Between Phenotypes and Genotypes Hypertension, February 1, 2002; 39(2): 332 - 336. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Hassan, N. Ali, Y. Dong, N. D. Carter, and H. S. Markus Atrial natriuretic peptide gene G664A polymorphism and the risk of ischemic cerebrovascular disease Neurology, November 13, 2001; 57(9): 1726 - 1728. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. van Eickels, C. Grohe, J. P.M. Cleutjens, B. J. Janssen, H. J.J. Wellens, and P. A. Doevendans 17{beta}-Estradiol Attenuates the Development of Pressure-Overload Hypertrophy Circulation, September 18, 2001; 104(12): 1419 - 1423. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. L Vesely Atrial natriuretic peptides in pathophysiological diseases Cardiovasc Res, September 1, 2001; 51(4): 647 - 658. [Full Text] [PDF]
|
|
|
|
|
|
L. Sironi, E. Tremoli, I. Miller, U. Guerrini, A. M. Calvio, I. Eberini, M. Gemeiner, M. Asdente, R. Paoletti, and E. Gianazza Acute-Phase Proteins Before Cerebral Ischemia in Stroke-Prone Rats : Identification by Proteomics Stroke, March 1, 2001; 32(3): 753 - 760. [Abstract] [Full Text] [PDF]
|
|