Cardiovascular Research Advance Access originally published online on September 29, 2008
Cardiovascular Research 2009 81(3):618-626; doi:10.1093/cvr/cvn263
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Genetic analysis of salt-sensitive hypertension in Dahl rats reveals a link between cardiac fibrosis and high cholesterol
1 Department of Clinical Pharmacology and Toxicology CBF/CCM, CharitéCentrum für Therapieforschung, Charité – Universitätsmedizin Berlin, Berlin, Germany
2 Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany
3 Department of Clinical Chemistry, University of Freiburg, Freiburg, Germany
4 Leibniz-Institut für Arterioskleroseforschung, Münster, Germany
* Corresponding author. Tel: +49 30 450 525 112; fax: +49 30 450 525 932. E-mail address: norbert.wendt{at}charite.de
Aims: Previously we confirmed an important role of rat chromosome 19 (RNO19) for salt-sensitive hypertension and target organ damage in male Dahl salt-sensitive rats (SS rats). The aim of this study was to further analyse the basis of left ventricular (LV) fibrosis development in both male and female rats in this model. To this end we utilized a consomic SS-19SHR rat strain in which RNO19 was transferred from spontaneously hypertensive rats (SHR) into the susceptible background of SS.
Methods and results: We compared the effects of low- (0.2% NaCl) and high-salt (4% NaCl) diet on the development of hypertension, blood lipids and LV fibrosis in male and female SS, SHR, and SS-19SHR rats. Systolic blood pressure was significantly lower in male and female SS-19SHR compared with SS under both diets (P < 0.001). Relative LV weight was similarly reduced in SS-19SHR compared with SS in either sex. Plasma cholesterol concentrations were significantly elevated in high-salt fed male and female SS (141 ± 6 and 110 ± 7 mg/dL) compared with SHR (47 ± 2 and 62 ± 8 mg/dL, P < 0.001) and were significantly lowered in male and female consomic rats (100 ± 7 and 87 ± 3 mg/dL). Both LV interstitial fibrosis (LVIF) and perivascular fibrosis (LVPF) were significantly reduced in high-salt male and female SS-19SHR. A significant correlation between cholesterol concentrations and LVPF (r = 0.464) and LVIF (r = 0.401, P < 0.0001, respectively) was detected. Fibrosis parameters demonstrated no correlation with blood pressure, LV weight or plasma triglycerides concentrations. LV immunohistochemistry analysis showed a significant higher number of ED-1 positive cells in SS compared with SS-19SHR. Depositions of collagen I and fibronectin were also greater in LV tissue of SS compared with SS-19SHR.
Conclusion: Our findings point to a link between hypercholesterolemia and LV fibrosis in salt-sensitive hypertension of SS rats which is genetically modulated by RNO19.
KEYWORDS Cardiac fibrosis; Inflammation; Hypertension; Hypercholesterolemia; Genetics; Salt-sensitivity
Time for primary review: 26 days