Jans D M, Martinet W, Van De Parre T J L, Herman A G, Bult H, Kockx M M, De Meyer G R Y
Division of Pharmacology, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium.
Cardiovasc Hematol Disord Drug Targets. 2006 Mar;6(1):21-34. doi: 10.2174/187152906776092695.
Macrophage activation in atherosclerotic plaques plays a role in plaque destabilization, rupture and subsequent atherothrombosis. Platelet phagocytosis that occurs within human atherosclerotic plaques can activate macrophages and it has been suggested that the platelet constituent amyloid precursor protein (APP) is involved. Recent studies show that amyloid beta (Abeta), a peptide extensively studied in Alzheimer's disease and that is cleaved from APP by beta- and gamma-secretase, and/or Abeta-like peptides are also present in human atherosclerotic plaques, in particular in activated, inducible nitric oxide synthase (iNOS) expressing perivascular macrophages that had phagocytized platelets. In vitro studies confirm that platelet phagocytosis leads to macrophage activation and suggest that platelet-derived APP is proteolytically processed to Abeta-like peptides, resulting in iNOS induction. In addition, non-steroidal anti-inflammatory drugs (NSAIDs) and HMG-CoA reductase inhibitors (statins), two classes of drugs reported to affect APP processing and Abeta formation in Alzheimer's disease, have been evaluated for their capacity to inhibit macrophage activation evoked by platelet phagocytosis. Remarkably, the same NSAIDs reported to alter gamma-secretase activity in Alzheimer's disease also reduce macrophage activation after platelet phagocytosis and inhibit formation of Abeta-containing peptides. From the statins investigated (fluvastatin, atorvastatin, simvastatin, pravastatin, lovastatin and rosuvastatin) only fluvastatin and atorvastatin selectively inhibit macrophage activation after platelet phagocytosis, possibly through inhibition of Rho activity. Taken together, these new findings point to the involvement of platelet-derived APP in macrophage activation in atherosclerosis and suggest a biochemical link between atherosclerosis and Alzheimer's disease. Accordingly, drugs interfering with APP processing might have an impact on both diseases.
动脉粥样硬化斑块中的巨噬细胞活化在斑块不稳定、破裂及随后的动脉粥样硬化血栓形成中发挥作用。发生在人类动脉粥样硬化斑块内的血小板吞噬可激活巨噬细胞，并且有人提出血小板成分淀粉样前体蛋白（APP）参与其中。最近的研究表明，淀粉样β蛋白（Aβ），一种在阿尔茨海默病中被广泛研究且由β和γ分泌酶从APP裂解而来的肽，和/或Aβ样肽也存在于人类动脉粥样硬化斑块中，特别是在已吞噬血小板的、表达诱导型一氧化氮合酶（iNOS）的血管周围活化巨噬细胞中。体外研究证实血小板吞噬导致巨噬细胞活化，并表明血小板衍生的APP被蛋白水解加工成Aβ样肽，从而导致iNOS诱导。此外，已评估了两类据报道会影响阿尔茨海默病中APP加工和Aβ形成的药物——非甾体抗炎药（NSAIDs）和HMG-CoA还原酶抑制剂（他汀类药物）抑制血小板吞噬引起的巨噬细胞活化的能力。值得注意的是，据报道在阿尔茨海默病中改变γ分泌酶活性的相同NSAIDs也能减少血小板吞噬后的巨噬细胞活化并抑制含Aβ肽的形成。在所研究的他汀类药物（氟伐他汀、阿托伐他汀、辛伐他汀、普伐他汀、洛伐他汀和瑞舒伐他汀）中，只有氟伐他汀和阿托伐他汀选择性抑制血小板吞噬后的巨噬细胞活化，可能是通过抑制Rho活性。综上所述，这些新发现表明血小板衍生的APP参与动脉粥样硬化中的巨噬细胞活化，并提示动脉粥样硬化与阿尔茨海默病之间存在生化联系。因此，干扰APP加工的药物可能对这两种疾病都有影响。
