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. 1997 Dec 23;94(26):14730-5.
doi: 10.1073/pnas.94.26.14730.

Hypertension, cardiac hypertrophy, and sudden death in mice lacking natriuretic peptide receptor A

P M Oliver  1 , J E Fox, R Kim, H A Rockman, H S Kim, R L Reddick, K N Pandey, S L Milgram, O Smithies, N Maeda
Affiliations

Hypertension, cardiac hypertrophy, and sudden death in mice lacking natriuretic peptide receptor A

P M Oliver et al. Proc Natl Acad Sci U S A. .

Abstract

Natriuretic peptides, produced in the heart, bind to the natriuretic peptide receptor A (NPRA) and cause vasodilation and natriuresis important in the regulation of blood pressure. We here report that mice lacking a functional Npr1 gene coding for NPRA have elevated blood pressures and hearts exhibiting marked hypertrophy with interstitial fibrosis resembling that seen in human hypertensive heart disease. Echocardiographic evaluation of the mice demonstrated a compensated state of systemic hypertension in which cardiac hypertrophy and dilatation are evident but with no reduction in ventricular performance. Nevertheless, sudden death, with morphologic evidence indicative in some animals of congestive heart failure and in others of aortic dissection, occurred in all 15 male mice lacking Npr1 before 6 months of age, and in one of 16 females in our study. Thus complete absence of NPRA causes hypertension in mice and leads to cardiac hypertrophy and, particularly in males, lethal vascular events similar to those seen in untreated human hypertensive patients.

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Figures

Figure 1
Figure 1
Targeted disruption of the Npr1 gene. (A) The top line shows the structure of the Npr1 gene containing 22 exons spanning approximately 18 kb. The targeting construct (middle line) was designed to replace exon 1 through intron 1 with a neomycin resistance gene (NEO). TK indicates the Herpes simplex thymidine kinase gene, which with NEO allowed selection in a medium containing ganciclovir (Ganc) and G418. The cloning vector is represented by a wavy line. The bottom line shows the targeted locus. (B) A Western blot, using an antibody against the extracellular domain of rat NPRA, of the membrane fraction of kidney extracts prepared from Npr1 −/− (homozygous mutant) and +/+ (wild type) mice. The 135-kDa NPRA protein, present in the wild-type mice but absent in the mutants, is indicated, as is an unidentified cross-reacting protein of 97 kDa that is equally present in mice of both genotypes. (C) An autoradiogram showing the absence or presence of the 135-kDa NPRA after photoaffinity labeling with 4-azidobenzoyl [125I]-ANP in plasma membrane preparations of lung tissue from Npr1 −/− and wild-type (+/+) mice. The positions of the 135-kDa NPRA and 70-kDa natriuretic peptide receptor C radiolabeled bands are indicated.
Figure 2
Figure 2
Blood pressures, heart weights, and survivals of mutant and wild-type mice. (A) Blood pressures as a function of Npr1 genotype and dietary salt. Mean blood pressures measured by a noninvasive computerized tail-cuff method in conscious young adult mice aged 95–115 days are shown for male (n = 12 per genotype) and female (n = 20 per genotype) Npr1 −/− (solid bars) and +/+ (open bars) animals on a low (0.05% NaCl), intermediate (2% NaCl), or high (8% NaCl) salt diet. SEMs are indicated above the bars. ∗, P < 0.001 vs. wild-type controls by ANOVA. (B) Heart weights as a percent of total body weight of 3-month-old mice. Individual values are represented as squares (males) and circles (females), and mean values are indicated by horizontal lines. ∗, P < 0.001 and †, P < 0.01 vs. wild-type controls by two-tailed t test. (C) The percentage survival of male (M) and female (F) Npr1 −/− animals and wild-type (+/+) controls as a function of age.
Figure 3
Figure 3
M-mode echocardiographic tracings from an Npr1 +/+ and an Npr1 −/− mouse. ECG, electrocardiogram; IVS, interventricular septal wall; PW, posterior wall. The longer and shorter vertical bars illustrate the left ventricular end diastolic and end systolic dimensions, respectively. The ECG is used for timing purposes and, because it is not calibrated, cannot be used to assess conduction patterns.
Figure 4
Figure 4
Histological analysis of tissues from Npr1 −/− male mice and wild-type controls. (A–E) Heart tissues from euthanized animals stained with Masson’s trichrome. Hearts were fixed without diastole arrest and with no intracardiac pressure, consequently the in vivo dilatation of the Npr1 −/− hearts was not preserved. (A) ×9 and (C) ×175 magnification of transverse sections of the heart from a 3.5-month-old wild-type male. (B) ×9 and (D) ×175 magnification of sections from a 3.5-month-old Npr1 −/− male. Fibrotic regions stain blue. (E) ×175 magnification of a section of a 4-month-old Npr1 −/− male showing dying myocytes (blue). (F) ×45 magnification of the aortic dissection from a deceased 3.5-month-old Npr1 −/− male, stained with trichrome-elastin stain to show elastic and connective tissue. The platelet-fibrin strands in the clot in the lower left quadrant show that some bleeding had occurred before death of the mouse.
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References

    1. Atlas S A, Kleinert H D, Camargo M J, Januszewicz A, Sealey J E, Laragh J H, Schilling J W, Lewicki J A, Johnson L K, Maack T. Nature (London) 1984;309:717–719. - PubMed
    1. Lang R E, Tholken H, Ganten D, Luft F C, Ruskoaho H, Unger T. Nature (London) 1985;314:264–266. - PubMed
    1. Garbers D L, Lowe D G. J Biol Chem. 1994;269:30741–30744. - PubMed
    1. Sagnella G A, MacGregor G A. In: Textbook of Hypertension. Swales J D, editor. Oxford: Blackwell Scientific; 1994. pp. 273–288.
    1. Espiner E A, Richards A M, Yandle T G, Nicholles M G. Endocrinol Metab Clinics N America. 1995;24:481–509. - PubMed

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