We sought to elucidate the effect of ApoA-II deficiency around the distribution of lipoprotein particles and other apolipoproteins during APR. small HDL in mice. Our observations uncovered the crucial functions of ApoA-II in inflammation, serum lipoprotein stability and AA amyloidosis morbidity, and prompt concern of therapies for AA and other amyloidoses, whose precursor proteins are associated with circulating HDL particles. Introduction Amyloidosis is usually a group of diseases characterized by extracellular or intracellular deposition of insoluble amyloid fibrils, which are aggregates formed from normally soluble proteins via conformational changes caused by various mechanisms1,2. Several serious human diseases such as Alzheimers disease, type II diabetes, prion disease and familial amyloid polyneuropathy (FAP) are associated with amyloid fibril deposition3. Reactive amyloid A (AA) amyloidosis is a systemic type of amyloidosis and occurs in domestic, laboratory and wild animals, as well as in humans4C6. AA amyloidosis is usually a major complication of chronic inflammation in patients with rheumatoid arthritis and serious infection diseases. As an acute phase plasma protein predominantly synthesized in the liver7,8, serum amyloid A (SAA) is usually deposited extracellularly as amyloid fibrils, which leads to tissue structure damage and dysfunction of various organs, including the liver, spleen, kidney and heart, among others9,10. SAA was first identified as a serum protein that cross-reacts with antibodies against AA protein11C13. During the acute phase reaction (APR) of inflammation, the concentration of plasma SAA, as a high density lipoprotein (HDL) associated apolipoprotein, may increase up to ~1000-fold. SAA is an evolutionarily conserved protein, but its function has not been completely elucidated. Rabbit Polyclonal to CNGB1 As a biomarker for inflammation, its role in cancer, cardiovascular disease, and inflammatory processes remains controversial14,15. However, its adverse role has been established in the pathogenesis of AA amyloidosis. Sustained high levels of SAA result in tissue deposition of the N-terminal fragments of SAA as amyloid fibrils. In mice, AA amyloid deposition can be experimentally induced by multiple injections of silver nitrate (AgNO3), casein or lipopolysaccharide (LPS), resulting in amazing elevation and maintenance of high levels of plasma SAA16. Amyloid enhancing factor (AEF) and AA amyloid fibrils have Imisopasem manganese been used to induce and/or accelerate AA amyloidosis in mice and other animals, such as hens and rabbits17C19. In addition to the stimulation of reverse cholesterol transport from extra-hepatic tissue to the liver, HDL is known for its preventive functions in cardiovascular disease through anti-oxidant and anti-inflammatory effects20,21. Apolipoprotein A-II (ApoA-II) is the second most abundant protein component of HDL; however, its functions in HDL function and metabolism remain unclear22. ApoA-II is usually reported to be more hydrophobic than apolipoprotein A-I (ApoA-I), and is closely associated with modulation of HDL metabolism and alteration of HDL conformation by interacting with ApoA-I and other apolipoproteins23C25. In mice, ApoA-II is a serum precursor of amyloid fibrils (AApoAII) in age-associated systemic amyloidosis (AApoAII amyloidosis)26,27. Our previous study found that mouse SAA, ApoA-I and Imisopasem manganese ApoA-II interact with each other during AA and AApoAII amyloidosis28,29. It has been reported that during APR, elevated SAA binds to HDL and decreases levels of ApoA-I and ApoA-II, leading to alteration of HDL particle size11,30,31. To investigate the potential role of ApoA-II in lipoprotein particle distribution and progression of AA amyloidosis, we induced AA amyloidosis by co-injection of AA amyloid fibrils (AEF) and AgNO3 (inflammation inducer) in wild type (WT), ApoA-II deficient (mice. Imisopasem manganese Moreover, ApoA-II deficiency Imisopasem manganese resulted in dramatic alteration of lipoprotein particles and redistribution of apolipoprotein in lipoproteins. These results suggest an important role of ApoA-II in inflammation, lipoprotein metabolism and AA amyloidosis. Results AA amyloid deposition was suppressed in mice After co-injection of AgNO3 and AA fibrils, tissue sections from various organs were stained with Congo red, and amyloid deposition (amyloid score: AS and amyloid index: AI) was subsequently determined by green birefringence under polarizing microscopy. The liver of WT and mice and the spleen of WT mice showed AA amyloid deposition 12?h and 1 d after injection (Fig.?1 and Supplementary Fig.?1). After 3 to 10 d of injection, AA amyloid deposition had expanded from the liver and spleen to the stomach, intestine, lung and kidney (Fig.?2). ASs in these organs were significantly less in mice than in WT mice (Figs?1 and ?and2).2). The degree of amyloid deposition in the whole body (AI) was significantly reduced in mice at 12?h, 1 d, 3 d and 10 d after treatment (Fig.?1). Open.

By admin