Periaortic Adipose-derived Interleukin-6Contributes To Arterial Stiffness In Low-density Lipoprotein Receptor Deficient Mice

Cardiovascular disease is a common chronic disease, and it has the highest rate ofmorbidity and mortality. It was reported, until2030, there would be23.3million peopleworldwide dying from cardiovascular disease. Globally, cardiovascular disease has led toenormous health care expenditure, especially in low-income developing countries. China isexpected to spend$558billion in the prevention and treatment of cardiovascular diseaseduring2005to2015. Therefore, it is very important to find a new method to prevent and treatthe occurrence and development of cardiovascular disease. Arterial stiffness is closely relatedto cardiovascular events, it also indicates the incidence of cardiovascular disease. Therefore,there is great significance to study the mechanism and influencing factors of arterial stiffnessfor prevention and treatment of cardiovascular disease. Hyperlipidemia often companies withincreased arterial stiffness to cause cardiovascular disease, but it is unknown whetherhyperlipidemia increases arterial stiffness by affecting the structural proteins of the artery.Studies showed that PAT could release inflammatory factors like IL-6and IL-6was theimportant factor of artery stiffness. Thus, we presume that hyperlipidemia increase arterystiffness by IL-6which is released by PAT.Low-density lipoprotein receptor deficient mice (LDLr-/-mice) is a typical model ofhyperlipidemia, we chose LDLr-/-mice as the main object of this project, and to study theinfluence and mechanism of hyperlipidemia on arterial stiffness. Firstly, to identify thathyperlipidemia increases arterial stiffness by affecting the structural proteins of the artery, wecompared LDLr-/-mice with wild type (WT) mice to test the body weight, heart weight, fatbody mass, lean body mass, systolic blood pressure, lipid level, aPWV, elastic modulus andthe levels of structural proteins relative to arterial stiffness(collagen, AGEs, elastic protein).Second, to clarify that LDLr-/-mice have increased intrinsic mechanical stiffness in aorticsegments by PAT, we divided LDLr-/-mice and WT mice to4groups:①WT,②WT+PAT,③LDLr-/-,④LDLr-/-+PAT, and we tested the aortic elastic modulus and the expression ofcollagen I, elastic protein, AGEs of the four groups. Third, we compared the aortic elastic modulus from WT mice which was cultured in conditioned medium from PAT of WT mice orfrom PAT of LDLr-/-mice. Then, we tested the IL-6of conditioned medium from PAT ofLDLr-/-mice and PAT of WT, and we also tested the aortic elastic modulus of the WT micecultured in IL-6conditioned medium or DMEM medium. Finally, we observed the influenceof IL-6antagonist on the aortic elastic modulus of LDLr-/-mice with or without PAT.These results showed that (1)There was no significant difference between LDLr-/-groupand WT group in the body weight, heart weight, fat body mass, lean body mass and systolicblood pressure(P>0.05).(2)The levels of total cholesterol and triglyceride of LDLr-/-groupwere much higher than those of WT group (P<0.05).(3) PWV, elastic modulus and the levelsof structural proteins of LDLr-/-mice were much higher than those of WT group (P<0.05).(4)The intrinsic mechanical stiffness in aortic segments with PAT from LDLr-/-mice was muchhigher (P<0.05).(5) Compared with PAT conditioned medium from WT mice, the intrinsicmechanical stiffness in aortic segments from WT mice cultured in PAT conditioned mediumfrom LDLr-/-mice was much higher(P<0.05).(6) The expression of collagen I in the mediaand adventitia of aorta and the expression of AGEs in the adventitia of aorta with PAT fromLDLr-/-were much higher, but the expression of elastic protein was much lower (P<0.05).(7)The area and diameter of PAT from LDLr-/-mice was much larger than that from WT mice(P<0.05).(8) There was much more influence of PAT conditioned medium from LDLr-/-miceon the intrinsic mechanical stiffness in aortic segments than that of subcutaneous adiposetissue or epididymal adipose tissue (P<0.05).(9) The PAT from LDLr-/-mice released moreIL-6than that from WT mice, and IL-6increased aortic stiffness. IL-6antagonist couldrelieve the increasing arterial stiffness which was induced by PAT (P<0.05).Therefore, we could get these conclusions:(1)There was imbalance of aortic structuralproteins from LDLr-/-mice, and the aortic stiffness of LDLr-/-mice was much higher than WTmice.(2) PAT from LDLr-/-mice could increase arterial stiffness.(3) The impact of PAT fromLDLr-/-mice on intrinsic mechanical stiffness in aortic segments was much stronger thansubcutaneous adipose tissue and epididymal adipose tissue.(4) PAT from LDLr-/-miceincreased the intrinsic mechanical stiffness in aortic segments by releasing IL-6.