Mechanisms regulating the atherogenic activities of serum amyloid A

急性期血清淀粉样蛋白A（SAA）不仅可以预测心血管疾病事件（CVD）， 在动脉粥样硬化的发展中起着因果作用。SAA是分泌蛋白家族， 血浆中的浓度在全身炎症反应期间增加1000倍或更多， 恢复到几乎无法检测的水平。然而，SAA在慢性炎症中也持续升高， 糖尿病、肥胖症、类风湿性关节炎等疾病。而肝脏是SAA的主要来源 在急性炎症反应期间，也已经记录了肝外表达。最值得注意的是， 脂肪组织被认为是肥胖人全身SAA的重要来源。已经认识 几十年来，SAA的血浆水平预测人类的心血管风险。最近，我们的团队 确定SAA在apoE缺陷小鼠的动脉粥样硬化中起致病作用。根据许多 根据多个实验室的报告，SAA在体外产生了无数的影响，预计会加剧 炎症和动脉粥样硬化。然而，这些已发表的研究大多调查了无脂质SAA， 忽略了在循环中未检测到无脂质SAA的事实。在大多数情况下，血浆SAA 发现与高密度脂蛋白（HDL）部分相关，越来越多的证据表明， HDL抑制SAA的促炎活性。因此，HDL的一个功能可能是螯合和 中和SAA并限制体内炎症的传播。值得注意的是，SAA也可以在apoB上检测到。 颗粒，特别是在心血管疾病风险增加的人群中。虽然 SAA与非HDL脂蛋白相关的病理生理学意义尚不清楚，我们 表明含apoB的脂蛋白上的SAA增强了它们的蛋白聚糖结合，这可能导致 增加血管滞留。综上所述，这些观察使我们提出，亲- SAA的炎性/促动脉粥样硬化活性受影响SAA与炎性/促动脉粥样硬化活性之间平衡的因素调节。 HDL-SAA、极低密度脂蛋白/低密度脂蛋白-SAA和无脂SAA。为了验证这个假设， 我们已经开发了关键的研究工具，包括具有可诱导的组织特异性SAA的新型小鼠模型 表达，以实现三个全面和互动的目的：目的1）确定是否HDL重塑 因素（例如，胆固醇酯转移蛋白，磷脂酶A2和氧化）导致释放 从富含SAA的HDL中提取生物活性SAA;目的2）确定SAA是否与apoB相关 脂蛋白在体外和体内增加其致动脉粥样硬化性;和目的3）确定SAA的组织来源是否 （肝脏相对于脂肪组织）影响其脂蛋白分布和/或其在体内的促动脉粥样硬化作用。的 该提案的结果将验证SAA作为心血管疾病的治疗靶点，并将开发 SAA脂蛋白分布作为风险的潜在生物标志物。

Acute phase serum amyloid A (SAA) is not only predictive of cardiovascular disease events (CVD) but also plays a causal role in the development of atherosclerosis. SAA is a family of secreted proteins whose concentration in the plasma increases 1000-fold or more during a systemic inflammatory response before returning to near undetectable levels. However, SAA is also persistently elevated in chronic inflammatory conditions such as diabetes, obesity, rheumatoid arthritis, etc. While the liver is the major source of SAA during an acute inflammatory response, extra-hepatic expression has also been documented. Most notably, adipose tissue is thought to be an important source of systemic SAA in obese humans. It has been recognized for decades that plasma levels of SAA predict cardiovascular risk in humans. More recently, our group determined that SAA plays a causative role in atherosclerosis in apoE-deficient mice. According to numerous reports by multiple laboratories, SAA exerts a myriad of effects in vitro that would be expected to exacerbate inflammation and atherosclerosis in vivo. However, most of these published studies investigated lipid-free SAA, overlooking the fact that lipid-free SAA is not detected in the circulation. In most circumstances, plasma SAA is found associated with the high-density lipoprotein (HDL) fraction, and accumulating evidence demonstrates that HDL inhibits SAA’s pro-inflammatory activity. Thus, one function of HDL may be to sequester and neutralize SAA and limit the propagation of inflammation in vivo. Notably, SAA can also be detected on apoB particles, particularly in human populations with increased risk for cardiovascular disease. Although the pathophysiological significance of the association of SAA with non-HDL lipoproteins is not known, we have shown that SAA on apoB-containing lipoproteins augments their proteoglycan binding, which could lead to increased vascular retention. Taken together, these observations lead us to propose that the pro- inflammatory/pro-atherogenic activities of SAA are regulated by factors that influence the equilibrium between HDL-SAA, very low-density lipoprotein/low-density lipoprotein-SAA, and lipid-free SAA. To test this hypothesis, we have developed critical research tools, including novel mouse models with inducible, tissue-specific SAA expression, to achieve three comprehensive and interactive aims: Aim 1) Determine whether HDL remodeling factors (e.g., cholesterol ester transfer protein, phospholipase A2 and oxidation) leads to the release of bioactive SAA from SAA-enriched HDL; Aim 2) Determine whether the association of SAA on apoB lipoproteins increases their atherogenicity in vitro and in vivo; and Aim 3) Determine if the tissue source of SAA (liver versus adipose tissue) influences its lipoprotein distribution and/or its pro-atherogenic effects in vivo. The results of this proposal will validate SAA as a therapeutic target in cardiovascular disease, and will develop SAA lipoprotein distribution as a potential biomarker of risk.