Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0851184 (thinning)
 11,252 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Deposition of amyloid beta-peptide (Abeta) in cerebral vessel walls (cerebral amyloid angiopathy, CAA) is very frequent in Alzheimer's disease and occurs also as a sporadic disorder. Here, we describe significant CAA in addition to amyloid plaques, in aging APP/Ld transgenic mice overexpressing the London mutant of human amyloid precursor protein (APP) exclusively in neurons. The number of amyloid-bearing vessels increased with age, from approximately 10 to >50 per coronal brain section in APP/Ld transgenic mice, aged 13 to 24 months. Vascular amyloid was preferentially deposited in arterioles and ranged from small focal to large circumferential depositions. Ultrastructural analysis allowed us to identify specific features contributing to weakening of the vessel wall and aneurysm formation, ie, disruption of the external elastic lamina, thinning of the internal elastic lamina, interruption of the smooth muscle layer, and loss of smooth muscle cells. Biochemically, the much lower Abeta42:Abeta40 ratio evident in vascular relative to plaque amyloid, demonstrated that in blood vessel walls Abeta40 was the more abundant amyloid peptide. The exclusive neuronal origin of transgenic APP, the high levels of Abeta in cerebrospinal fluid compared to plasma, and the specific neuroanatomical localization of vascular amyloid strongly suggest specific drainage pathways, rather than local production or blood uptake of Abeta as the primary mechanism underlying CAA. The demonstration in APP/Ld mice of rare vascular amyloid deposits that immunostained only for Abeta42, suggests that, similar to senile plaque formation, Abeta42 may be the first amyloid to be deposited in the vessel walls and that it entraps the more soluble Abeta40. Its ability to diffuse for larger distances along perivascular drainage pathways would also explain the abundance of Abeta40 in vascular amyloid. Consistent with this hypothesis, incorporation of mutant presenilin-1 in APP/Ld mice, which resulted in selectively higher levels of Abeta42, caused an increase in CAA and senile plaques. This mouse model will be useful in further elucidating the pathogenesis of CAA and Alzheimer's disease, and will allow testing of diagnostic and therapeutic strategies.
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PMID:Prominent cerebral amyloid angiopathy in transgenic mice overexpressing the london mutant of human APP in neurons. 1102 33

Between 1998 and 1999 we suggested a role for cysteine proteases, particularly cathepsins S and K, in atherosclerosis and abdominal aortic aneurysm (AAA) formation. We also demonstrated the presence and activity of cathepsins S, K, and L in atherosclerotic and aneurysmal lesions in humans. Features unique to this family of extracellular enzymes indicate its likely participation in these vascular diseases. As very potent elastolytic enzymes, cathepsins are strong candidates as key participants in aneurysm development. Importantly, cathepsins express very high elastolytic activity in AAA due to reciprocal correlation with cystatin C, their most abundant endogenous inhibitor. Two opposite processes coexist in aneurysmal tissue: overexpression of elastolytic cathepsins, and severe suppression of cystatin C, probably due to differentially regulated expression and secretion of cathepsins and their inhibitors in response to inflammatory cytokines. Involvement of cathepsins in microvessel formation, a pathophysiological marker of human AAA, and programmed cell death (apoptosis), increases the likelihood of cathepsin participation in AAA formation and growth. We also summarize here results obtained in our and other laboratories that demonstrated reduced atherosclerosis and AAA in in vivo models using mice lacking different cathepsins. Deficiency of cysteine protease inhibitor cystatin C in atherosclerosis-prone ApoE-null mice leads to the development of specific features of AAA such as thinning of the tunica media and aortic dilatation. Taken together, such findings in humans in vitro with different cell types and in vivo in genetically altered mice demonstrate the importance of cysteine protease/protease inhibitor balance in dysregulated arterial integrity and remodeling during atherosclerosis and aortic aneurysm formation.
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PMID:Do cathepsins play a role in abdominal aortic aneurysm pathogenesis? 1718 32

BACKGROUND The development of abdominal aortic aneurysm (AAA) is probably influenced by many factors. The role of some of these factors, such as intraluminal thrombus (ILT) or cystatin C serum levels, remains controversial. Proving their influence could have therapeutic implications for some patients with AAA. Associations between the rate of increase in diameter of an aneurysm and ILT, as well as other factors, including biochemical factors (C-Reactive Protein - CRP, cystatin C), age, sex, and comorbidities, could predict disease progression in individual patients. MATERIAL AND METHODS Seventy patients with small AAA were included into the study. The patients were followed using ultrasound and CT imaging. We evaluated aneurysm dimensions and aneurysm wall thickness, as well as ILT and its dimensions, aneurysm wall morphology, CRP, and cystatin C. RESULTS We observed significant growth of AAA and thinning of aneurysmal wall. Aneurysms over 4 cm grew significantly faster in the second year of observation. ILT grew together with AAA size. Age, sex, smoking, dyslipidemias, or controlled arterial hypertension had no influence on aneurysm progression rate. Changes in serum of CRP concentration did not reach statistical significance, but cystatin C levels did. CONCLUSIONS Presence and size of ILT, wall thickness, and cystatin C levels may be considered in prediction of AAA progression. ILT might exert a protective influence on the risk of aneurysm rupture. However, larger aneurysms containing larger thrombi grow faster and their walls undergo more rapid degradation, which in turn increases the risk of rupture. This matter requires further studies.
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PMID:Influence of Selective Biochemical and Morphological Agents on Natural History of Aneurysm of Abdominal Aorta Development. 2685 44