Differential effects of dietary sodium intake on blood pressure and atherosclerosis in hypercholesterolemic mice

Abstract

The amount of dietary sodium intake regulates the renin angiotensin system (RAS) and blood pressure, both of which play critical roles in atherosclerosis. However, there are conflicting findings regarding the effects of dietary sodium intake on atherosclerosis. This study applied a broad range of dietary sodium concentrations to determine the concomitant effects of dietary sodium intake on the RAS, blood pressure, and atherosclerosis in mice. Eight-week-old male low-density lipoprotein receptor -/- mice were fed a saturated fat-enriched diet containing selected sodium concentrations (Na 0.01%, 0.1%, or 2% w/w) for 12 weeks. Mice in these three groups were all hypercholesterolemic, although mice fed Na 0.01% and Na 0.1% had higher plasma cholesterol concentrations than mice fed Na 2%. Mice fed Na 0.01% had greater abundances of renal renin mRNA than those fed Na 0.1% and 2%. Plasma renin concentrations were higher in mice fed Na 0.01% (14.2 ± 1.7 ng/ml/30 min) than those fed Na 0.1% or 2% (6.2 ± 0.6 and 5.8 ± 1.6 ng/ml per 30 min, respectively). However, systolic blood pressure at 12 weeks was higher in mice fed Na 2% (138 ± 3 mm Hg) than those fed Na 0.01% and 0.1% (129 ± 3 and 128 ± 4 mmHg, respectively). In contrast, mice fed Na 0.01% (0.17 ± 0.02 mm(2)) had larger atherosclerotic lesion areas in aortic roots than those fed Na 2% (0.09 ± 0.01 mm(2)), whereas lesion areas in mice fed Na 0.1% (0.12 ± 0.02 mm(2)) were intermediate between and not significantly different from those in Na 0.01% and Na 2% groups. In conclusion, while high dietary sodium intake led to higher systolic blood pressure, low dietary sodium intake augmented atherosclerosis in hypercholesterolemic mice.

Fig. 1

Low dietary sodium led to higher plasma VLDL and IDL/LDL cholesterol concentrations in hypercholesterolemic mice. (A) Lipoproteins in plasma were resolved by size exclusion chromatography and measured using an enzymatic method. Triangles represent the mean values from 5-6 individual mice and bars represent S.E.M. (B) Plasma cholesterol concentrations of lipoprotein fractions were calculated using a non linear curve fitting method. Histobars represent means and bars represent S.E.M. Statistical analysis was performed using one way ANOVA. *P<.05 for comparisons with mice fed Na 2% (n=16–18/group).

Fig. 2

High dietary sodium increased systolic blood pressure in hypercholesterolemic mice. Systolic blood pressure was measured using a tail-cuff system at Week 0, 4, 8, and 12 during the selected dietary sodium feeding. Triangles represent means of weekly observations and bars represent S.E.M. As analyzed with one way repeated measures ANOVA, mice fed Na 2%, but not mice fed either Na 0.01% or Na 0.1%, had increased systolic blood pressure during the 12-week selected diet feeding. * and ^#P<.05 for comparisons with mice fed Na 0.01% and Na 0.1%, respectively (n=16-18/group).

Fig. 3

Low dietary sodium resulted in higher renal renin mRNA abundances and plasma renin concentrations. (A) mRNA abundance of renal renin was quantified with real-time PCR using ΔΔCt method (n=5/group). (B) Plasma renin concentrations were measured using radioimmunoassay in 9-10 mice/group. Data are mean± S.E.M. Statistical analysis was performed using one way ANOVA. * P<.01 for comparisons with mice fed Na 0.01%.

Fig. 4

Low dietary sodium led to greater atherosclerotic lesion areas in aortic roots. Atherosclerotic lesion areas were measured in aortic roots. Triangles represent average lesion areas throughout the aortic root (eight serial sections/aortic root; n=13–15/group) of each mouse. Circles represent the means, and bars are S.E.M. Statistical analysis was performed using one way ANOVA. There were no significant differences of mean lesion areas between mice fed Na 0.1% and mice fed either Na 0.01% or Na 2%.