Intermittent Cold Stress Enhances Features Of Atherosclerotic Plaque Instability In ApoE-deficient Mice

Backgrond：Clinical manifestations of atherosclerosis, including coronary arterydisease, cerebrovascular disease, and peripheral arterial disease, will occur in2of3men and1in2women after age40. Almost60%of deaths are due to acardiovascular disease (CVD) cause. In our country, the prevalence ofcardiovascular patients at the rising stage, according to statistics, at present hasreached230million people, that is, on average, one in every five adult peoplesuffering from heart disease. The country each year as many as3.5millionpatients died of cardiovascular disease. Previous studies have confirmed that theoccurrence of acute coronary syndrome (ACS) is mainly due to coronary arterycaused by the instability of atherosclerotic plaques, and the main characteristicof instability plaque is covered on the surface of the plaque, thin fibrous cap.According to epidemiological survey found that the death of coronaryheart disease events closely related to the temperature of the surroundingenvironment, as environmental temperature drop, the rising incidence of acutecoronary syndrome. Can also be found in the clinical work, in the cold winter,all kinds of morbidity and mortality of cardiovascular disease will risen. Butlow temperature affect the occurrence of acute coronary syndrome mechanismis unclear. So we propose a hypothesis: Chronic low temperature stimulationcauses plaque instability was associated with the thin fibrous cap of plaques.Objective:The cold weather is associated with an increased occurrence of acutecoronary events. However, the mechanisms underlying cold-induced heartattack has not been fully understood.Materials and Methods:Twenty male ApoE-deficient mice,8weeks of age, were subjectedto either control conditions or intermittent cold exposure for8weeks. M- ice in cold group were placed in a cold room at4°C for4hours per d-ay, while the mice in control group were kept in a room at24°C. After8weeks, triglycerides (TG),total cholesterol(TC),Low-density lipoproteincholesterol(LDL-C),high-density lipoprotein-cholesterol(HDL-C), Atheroscle-rotic plaque size, plaque collagen content and the expression of lymphoc-yte, macrophage, vascular smooth muscle cell,matrix metalloproteinase (MMP)-2, MMP-3,MMP-9,and MMP-14and the tissue inhibitor of MMP (TIMP)-1,and TIMP-2were determined.Results: Cold-exposed mice did not significantly differ from controlmice in body weight, fasting glucose concentration and plasma lipid levels,including triglyceride, total cholesterol, low-density lipoprotein andhigh-density lipoprotein. The hematoxylin and eosin-stained sections of theaortic root showed increased plaque size in cold group compared with controlgroup (p<0.01). Moreover, cold-treated mice exhibited significantly decreasedplaque collagen and vascular smooth muscle cell deposition and increasedmacrophage and lymphocyte content (p<0.05or p<0.01), the features ofatherosclerotic plaque stability. Additionally, matrix metalloproteinase(MMP)-2/MMP-9/MMP14protein expressions were significantly increased(p<0.05or p<0.01), whereas tissue inhibitor of MMP (TIMP)-1expression wasdecreased (p<0.05) after exposure to cold. The present study demonstrates thatchronic intermittent cold stress might increase atherosclerotic plaque size andpromote plaque instability in ApoE-deficient mice by changing the balance ofMMPs and TIMPs. These results might contribute to mechanistic insights intosudden cardiac death in cold environments.