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)

Atherosclerosis in a major leg artery leads to impaired blood supply, which normally progresses to critical limb ischemia. Atherosclerosis produces substantial alterations of structure and endothelial function in the large conduit arteries. Pressure unloading and ischemia in the distal vasculature bring about alterations in microvascular function. Resistance arteries undergo significant wall thinning and changes in their contractile regulation. Optimization of large artery dimensions by the small arteries through flow-mediated vasodilation is impaired. Angiogenesis is stimulated, which can result in the formation of major collateral feeder vessels in addition to small nutritive blood vessels. However, angiogenesis can also contribute to instability of atherosclerotic plaques, which ultimately leads to further deterioration in blood supply. Surgical bypass grafting to restore blood supply to the distal leg generates a sudden increase of pressure in the weakened resistance vasculature, leading to uncontrolled changes in capillary hydrostatic pressure, extravasation of fluid, and tissue edema. This review aims to highlight the importance of the resistance vasculature in critical limb ischemia and the interdependence of pathophysiological changes in the large conduit and small resistance arteries. The major unresolved question is why the physiological mechanisms that regulate vascular structure and function ultimately break down, leading to circulatory failure within the distal limb.
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PMID:Marriage of resistance and conduit arteries breeds critical limb ischemia. 1570 41

Werner syndrome (WS) is an autosomal recessive premature aging disease manifested by the mimicry of age-related phenotypes such as atherosclerosis, arteriosclerosis, cataracts, osteoporosis, soft tissue calcification, premature thinning, graying, and loss of hair, as well as a high incidence of some types of cancers. The gene product defective in WS, WRN, is a member of the RecQ family of DNA helicases that are widely distributed in nature and believed to play central roles in genomic stability of organisms ranging from prokaryotes to mammals. Interestingly, WRN is a bifunctional protein that is exceptional among RecQ helicases in that it also harbors an exonuclease activity. Furthermore, it preferentially operates on aberrant DNA structures believed to exist in vivo as intermediates in specific DNA transactions such as replication (forked DNA), recombination (Holliday junction, triplex and tetraplex DNA), and repair (partial duplex with single stranded bubble). In addition, WRN has been shown to physically and functionally interact with a variety of DNA-processing proteins, including those that are involved in resolving alternative DNA structures, repair DNA damage, and provide checkpoints for genomic stability. Despite significant research activity and considerable progress in understanding the biochemical and molecular genetic function of WRN, the in vivo molecular pathway(s) of WRN remain elusive. The following review focuses on the recent advances in the biochemistry of WRN and considers the putative in vivo functions of WRN in light of its many protein partners.
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PMID:Current advances in unraveling the function of the Werner syndrome protein. 1594 10

Dysfunctional vascular smooth muscle cell (VSMC) behaviour contributes to the pathogenesis of atherosclerosis and restenosis. Increased rates of VSMC apoptosis are thought to lead to thinning of the fibrous atherosclerotic plaque and thereby instability, while migration of VSMCs to the intima, and inappropriate VSMC proliferation, contribute to intimal thickening that occurs in atherosclerosis and restenosis. Studies, mainly in cancer and neuronal cells, have demonstrated that cell-cell adhesion by the cadherin:catenin complex modulates apoptosis, migration and proliferation. In contrast, until recently the involvement of this complex in the regulation of VSMC behaviour was relatively unstudied. In this review, evidence for the regulation of VSMC apoptosis, migration and proliferation by the cadherin:catenin complex will be discussed.
Atherosclerosis 2006 Sep
PMID:Cadherin:catenin complex: a novel regulator of vascular smooth muscle cell behaviour. 1643 74

We report 2 patients with left atrial (LA) myxoma with associated severe left ventricular (LV) dysfunction. Both presented with progressive effort intolerance without a history suggestive of acute coronary event. LA myxoma was diagnosed by transthoracic echocardiography, which also detected severe systolic dysfunction and LV dilatation. Regional wall motion abnormality and thinning were absent. Coronary angiograms also showed no occlusive disease, but distal ectasia was seen in 1 patient. Metabolic and endocrine causes of reversible LV dysfunction were excluded. Cardiac function improved following surgery for myxoma in 1 patient. LV dysfunction, thus far, has not been directly attributed to myxoma. Coronary embolization leading to myocardial infarction and coexisting coronary atherosclerosis are the recognized methods by which LV dysfunction manifests in myxoma. Our report suggests the possibility of reversible severe global LV dysfunction due to cardiodepressant effect of myxoma through as yet unclear mechanisms.
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PMID:Severe left ventricular dysfunction in left atrial myxoma--report of 2 cases. 1644 67

The ideal reconstructive method for the buccal mucosa should provide durable, stable coverage and a natural contour, while simultaneously minimizing morbidity of both the defect and donor sites. Since the first report of the anterolateral thigh flap in 1984, it has become one of the most commonly used flaps for the reconstruction of various soft-tissue defects. From March 2004-April 2005, 24 free anterolateral thigh flaps were used to reconstruct buccal defects, including the retromolar trigone and as far as the oral commissure, and in some cases with extension to the neighboring palatal region and tongue. The study comprised 1 female and 23 male patients, with ages ranging from 26-63 years (mean age, 45.8 years). Two flaps required reoperation due to vascular compromise, and both were salvaged with arterial and venous anastomosis revisions, giving an overall success rate of 100%. Primary thinning of the flap was performed in 10 cases. In 2 cases, additional vastus lateralis muscle was included in the flap to fill the large defect. In 2 cases, marginal necrosis with dehiscence of the flap was observed, one of these patients having a history of atherosclerosis and diabetes mellitus (marginal skin necrosis and infection of the donor area were also observed in this patient). In 2 patients, seroma collection was observed in the neck at the dissection site. Chart reviews showed that most patients had a history of betel-nut chewing (95.8%) or a combination of smoking and betel-nut chewing (79.2%). During the follow-up period of 4-12 months, a sufficient level of mouth-opening with interincisal distances of 34 mm, 44 mm, and 48 mm was achieved in all 3 cases reconstructed after release of the trismus. Although it has some variations in the vascular pedicle, irregularity in derivation from the main vessels, and minimal morbidity of the donor site, the anterolateral thigh flap, with its evident functional, structural, and cosmetic advantages, can be considered an excellent and ideal flap option, and a first choice for most buccal defects.
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PMID:Repair of buccal defects with anterolateral thigh flaps. 1649 56

Aneurysms of the coronary arteries are uncommon occurrences that usually develop secondary to atherosclerosis and are often asymptomatic. They are usually diagnosed incidentally during investigation for ischemic heart disease or at autopsy for sudden death. We present a case of a "giant" right coronary artery aneurysm (CAA) discovered incidentally at surgery. Pathological examination confirmed that this was a true aneurysm showing marked thinning of the media and fibrocalcific plaques with small, multifocal areas of lymphocytic infiltrates.
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PMID:A giant coronary artery aneurysm in the right coronary artery. 1669 28

Werner syndrome (WS) is a pleiotropic disease of premature aging involving short stature, tight, atrophied, and/or ulcerated skin; a characteristic 'birdlike' facies and high, squeaky or hoarse voice; premature greying and thinning of the hair; and early onset cataracts. Additional common symptoms include diabetes mellitus, hypogonadism, osteoporosis, osteosclerosis of the digits, soft tissue calcification, premature atherosclerosis, rare or multiple neoplasms, malformed teeth, and flat feet. Diagnosis can be difficult due to the variable presentation and rarity of the disorder. Transmission is usually autosomal recessive. The WS gene, WRN, is member of the RecQ DNA helicase family. Biallelic mutations of WRN are responsible for most patients. Although heterozygous missense mutations in the LMNA gene have been observed in severely affected WS patients, this only accounts for a small fraction of non-WRN patients. Eighteen WS cases were referred to us for molecular analysis. Eleven had definite and three had probable WS according to the University of Washington Registry clinical criteria. All exons of the WRN gene and their splice junctions were sequenced. Of the fourteen definite or probable cases, 11 had one or more WRN mutation. Thirteen different mutations were found, and ten of these were previously undescribed. There were few phenotypic differences between patients with WRN mutation(s) and those who met clinical criteria though lacking WRN mutations. However, patients with mutations tended to have more symptoms overall, and mutations were not observed in the two cases with cardiomyopathy.
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PMID:Werner syndrome and mutations of the WRN and LMNA genes in France. 1678 14

Vascular smooth muscle cell (VSMC) apoptosis occurs in many arterial diseases, including aneurysm formation, angioplasty restenosis and atherosclerosis. Although VSMC apoptosis promotes vessel remodeling, coagulation and inflammation, its precise contribution to these diseases is unknown, given that apoptosis frequently accompanies vessel injury or alterations to flow. To study the direct consequences of VSMC apoptosis, we generated transgenic mice expressing the human diphtheria toxin receptor (hDTR, encoded by HBEGF) from a minimal Tagln (also known as SM22alpha) promoter. Despite apoptosis inducing loss of 50-70% of VSMCs, normal arteries showed no inflammation, reactive proliferation, thrombosis, remodeling or aneurysm formation. In contrast, VSMC apoptosis in atherosclerotic plaques of SM22alpha-hDTR Apoe-/- mice induced marked thinning of fibrous cap, loss of collagen and matrix, accumulation of cell debris and intense intimal inflammation. We conclude that VSMC apoptosis is 'silent' in normal arteries, which have a large capacity to withstand cell loss. In contrast, VSMC apoptosis alone is sufficient to induce features of plaque vulnerability in atherosclerosis. SM22alpha-hDTR Apoe-/- mice may represent an important new model to test agents proposed to stabilize atherosclerotic plaques.
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PMID:Apoptosis of vascular smooth muscle cells induces features of plaque vulnerability in atherosclerosis. 1689 61

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

Conduit arteries become stiffer with age due to alterations in their morphology and the composition of the their major structural proteins, elastin and collagen. The elastic lamellae undergo fragmentation and thinning, leading to ectasia and a gradual transfer of mechanical load to collagen, which is 100-1000 times stiffer than elastin. Possible causes of this fragmentation are mechanical (fatigue failure) or enzymatic (driven by matrix metallo proteinases (MMP) activity), both of which may have genetic or environmental origins (fetal programming). Furthermore, the remaining elastin itself becomes stiffer, owing to calcification and the formation of cross-links due to advanced glycation end-products (AGEs), a process that affects collagen even more strongly. These changes are accelerated in the presence of disease such as hypertension, diabetes and uraemia and may be exacerbated locally by atherosclerosis. Raised MMP activity, calcification and impaired endothelial function are also associated with a high level of plasma homocysteine, which itself increases with age. Impaired endothelial function leads to increased resting vascular smooth muscle tone and further increases in vascular stiffness and mean and/or pulse pressure. The effect of increased stiffness, whatever its underlying causes, is to reduce the reservoir/buffering function of the conduit arteries near the heart and to increase pulse wave velocity, both of which increase systolic and pulse pressure. These determine the peak load on the heart and the vascular system as a whole, the breakdown of which, like that of any machine, depends more on the maximum loads they must bear than on their average. Reversing or stabilising the increased arterial stiffness associated with age and disease by targeting any or all of its causes provides a number of promising new approaches to the treatment of systolic hypertension and its sequelae, the main causes of mortality and morbidity in the developed world.
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PMID:Ageing of the conduit arteries. 1826 96


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