Inhibition Of Renin(Pro) Receptors On Atherosclerosis

BackgroundWith the reform of China,and the economy development rapidly,people’s living standards continue to improve and the pursuit of Western food,and eating habits gradually become closer to the West.Uncontrolled high-salt and high-calorie foods have greatly increased the number of people that suffering from obesity and cardiovascular disease in China.The mortality caused by cardiovascular and cerebrovascular diseases is much higher than that of cancer,which rank first among all major diseases.In China,the number of people suffering from cardiovascular and cerebrovascular diseases has increased year by year and the risk of death caused by cardiovascular and cerebrovascular diseases has also increased significantly.According to the incomplete statistics,about 290 million people suffering from various of cardiovascular and cerebrovascular diseases in China every year.More than 3.5 million deaths were caused,which is 40% of deaths caused by residents’ diseases.Abnormal increase in blood lipids in the human body,especially the increase of low-density lipoprotein cholesterol(LDL-C),is an important risk factor for cardiovascular and cerebrovascular diseases.The increased LDL-C can lead to abnormal deposition of LDL in the vessel,and increased oxidative LDL,macrophage infiltration,promoted foam cell formation,increased inflammatory response and atherogenesis.In recent years,we have discovered a new regulator of lipid metabolism,the renin(pro)receptor [(P)RR].It is involved in the regulation of blood pressure and it is an important member of the renin-angiotensin-aldosterone system.In the experiment,we have administered C57BL/6J mouse subcutaneously(P)RR inhibitors,while giving mouse a high-fat diet for 16 weeks.Compared to control mouse,we found a significant decrease in cholesterol and triglyceride in mouse plasma.Based on this experiment,we propose that inhibition(P)RR in vivo,can reduce atherosclerosis by lowering the cholesterol and triglycerides in blood lipids.ObjectiveInhibition the expression of(P)RR in mouse can regulate lipid metabolism and reduce cholesterol and triglyceride in plasma,in order to determine whether inhibition of(P)RR expression can also improve atherosclerosis in vivo.Methods and ResultsEight-week-old male LDL receptor knockout mouse and ApoE knockout mouse were injected subcutaneously(P)RR ASO dose for 30 mg/kg/week for the first four weeks and then dose reduce to 15 mg/kg/week for the other weeks;dose of G-(P)RR ASO is 3.0 mg/kg/week for the first four weeks,then dose reduce to 1.5 mg/kg/week for the other weeks,and the control mice were injected with the same volume of saline.All mouse were given high-fat diet with 16 weeks.At the initial week and even weeks,the mice were fasted for 6 hours and collected blood samples by submandibular.At the end of the experiment,the mouse tail tube system blood pressure meter was used to measure the systolic blood pressure of all the mouse.After the experiment,mouse were euthanized.The mouse were dissected,and the livers and hearts of the mouse were weighed and fixed with a fixing solution,and then pathological sections were prepared.The area of atherosclerotic plaque on the tricuspid valve and the aorta of aortic root of the mouse was statistically analyzed using computer software Image J.Compared with the control group of LDL receptor knockout mouse,mouse injected with(P)RR ASO and G-(P)RR ASO had significantly lower plasma cholesterol and triglyceride levels,but the atherosclerosis hardening did not reduce significantly.There was no change in systolic blood pressure,but several atherosclerosis-associated secretory factors in plasma,including apolipoprotein B and fibroblast growth factor 21,were affected by(P)RR inhibition.Compared with the control group ApoE knock out mouse injected with(P)RR ASO and G-(P)RR ASO had significantly lower plasma cholesterol and triglyceride levels,which inhibited the whole body.mouse with systemic(P)RR inhibited have significantly reduced aortic root tricuspid and aortic atherosclerotic plaque area,which can significantly reduce atherosclerosis,while inhibiting liver(P)RR,mouse had no significant reduction in the area of atherosclerotic plaque on the tricuspid valve and aorta of the aortic root,and atherosclerosis was not reduce.ConclusionsInhibition of systemic and hepatic(P)RR,significantly reduced plasma cholesterol and triglyceride levels in LDL receptor knockout mouse,but it did not reduce atherosclerosis.It may be related to the increased of ApoB secretion and the decrease of FGF-21 concentration which causing by inhibiting the(P)RR.Inhibition of systemic(P)RR reduced plasma cholesterol and triglyceride levels significantly in ApoE knockout mouse while reducing atherosclerosis significantly,while inhibiting hepatic(P)RR,mouse cholesterol and triglyceride levels were reduced significantly,but the atherosclerosis did not reduce.The specific molecular mechanism remains to be studied.