Mechanisms regulating the atherogenic activities of serum amyloid A

血清淀粉样蛋白 A 致动脉粥样硬化活性的调节机制

• 批准号: 10636872
• 负责人: Preetha Shridas
• 金额: $ 50.16万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-05 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10636872
• 关键词: Acute; Acute-Phase Proteins; Adipose tissue; Age; Anti-Inflammatory Agents; Apolipoprotein E; Apolipoproteins; Apolipoproteins B; Atherosclerosis; Binding; Biological Markers; Biology; Blood Vessels; Cardiovascular Diseases; Cessation of life; Cholesterol Ester Transfer Proteins; Chronic; Circulation; Clinical; Clinical Research; Development; Diabetes Mellitus; Dose; Equilibrium; Event; Extrahepatic; Family; Fatty acid glycerol esters; Generations; Goals; High Density Lipoproteins; Human; Impairment; In Vitro; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Interleukin-1 beta; Kidney; Laboratories; Lipids; Lipoprotein (a); Lipoprotein Binding; Lipoproteins; Liver; Low-Density Lipoproteins; Macrophage; Methotrexate; Mus; Natural Immunity; Obesity; Pathologic; Pathway interactions; Persons; Phase; Phospholipase A2; Plasma; Play; Population; Process; Protein Secretion; Proteoglycan; Publishing; Reporting; Research; Rheumatoid Arthritis; Risk; Risk Factors; Role; Series; Serum amyloid A protein; Signal Transduction; Site; Smoking; Source; Techniques; Testing; Tissues; Very low density lipoprotein; burden of illness; cardiovascular disorder risk; cardiovascular risk factor; experimental study; gain of function; high risk; in vivo; insight; loss of function; mouse model; novel; oxidation; particle; potential biomarker; response; systemic inflammatory response; therapeutic target; tissue injury; tool; uptake

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.

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），而且还可以预测心血管疾病的发生

项目成果

Management of Dyslipidemia in Endocrine Diseases.

• DOI: 10.1016/j.ecl.2022.02.003
• 发表时间: 2022-09
• 期刊: Endocrinology and metabolism clinics of North America
• 影响因子: 4.5

Deficiency of Acute-Phase Serum Amyloid A Exacerbates Sepsis-Induced Mortality and Lung Injury in Mice.

• DOI: 10.3390/ijms242417501
• 发表时间: 2023-12-15
• 期刊: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
• 影响因子: 5.6
• 作者: Ji, Ailing;Trumbauer, Andrea C.;Noffsinger, Victoria P.;Meredith, Luke W.;Dong, Brittany;Wang, Qian;Guo, Ling;Li, Xiangan;De Beer, Frederick C.;Webb, Nancy R.;Tannock, Lisa R.;Starr, Marlene E.;Waters, Christopher M.;Shridas, Preetha
• 通讯作者: Shridas, Preetha