Background Recently, over restrictive salt diet have shown to increase cardiovascular events, including atherosclerosis in normotensive individuals or in individuals with pre-hypertension. However, the surprised view attracted extensive attention and query. The authenticity and possible mechanism still should be given a deep discussion. Proprotein convertase subtilisin/kexin 9 (PCSK9), which is expressed in the wall of aorta and atherosclerotic plaque, has a closely relationship with atherosclerosis. Here, we investigated whether restrictive salt could accelerate development of atherosclerotic lesions via PCSK9 in ApoE^-/- mice.

Method Male mice aged 10-weeks and weighting between 20 to 25 g were allocated to receive an isocaloric diet with low-salt content (0.03%), low-salt diet (0.03%) combined with siRNA tail injection or normal salt content (0.3%) containing 6% fat. After 12 weeks of study, the basic metabolic index, including weight, blood pressure, urine sodiumand urine potassiumwere evaluated. The gross aorta was stained by oil red-O, and the quantification of plaque in cross section was detected by immunohistochemistry. The expression of PCSK9 was measured by Western blot.

Results Plaque accumulation of salt restriction diet for 12-weeks was 4.3 times higher than mice receiving normal salt in ApoE^-/-mice. Meanwhile, the mortality rate was extreme higher in the low salt group. Quantification of staining demonstrated a marked increasing inflammatory cells and larger necrotic core areas those could lead plaque instability in the low salt diet group. And the expression of PCSK9 in aorta showed that an increase of PCSK9 in a low salt group than normal salt diet. Group of low salt diet combined with PCSK9 siRNA could reduce the plaque development and the instability in ApoE^-/- mice.

Conclusions Over restrictive salt diet causes a high mortality, activates aortic PCSK9 expression to improve atherosclerotic plaque formation and leads to plaque instability as well. This finding provides mechanistic insights on low salt diet associated atherosclerosis.