Laminopathies and Atherosclerosis

Alshali, Khalid Z.; Hegele, Robert A.

doi:10.1161/01.atv.0000136392.59656.8b

Cited by 47 publications

(32 citation statements)

References 61 publications

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“…Arteriosclerosis is the leading cause of death in HGPS patients (Al-Shali & Hegele, 2004), and ultrastructural analysis of vascular (E) Left, HGPS cells had significantly lower migration speeds compared to healthy control fibroblasts (**P < 0.01). FTI treatment had no effect on migration speed.…”

Section: Discussionmentioning

confidence: 99%

Increased mechanosensitivity and nuclear stiffness in Hutchinson–Gilford progeria cells: effects of farnesyltransferase inhibitors

et al. 2008

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SummaryHutchinson-Gilford progeria syndrome (HGPS), reportedly a model for normal aging, is a genetic disorder in children marked by dramatic signs suggestive for premature aging. It is usually caused by de novo mutations in the nuclear envelope protein lamin A. Lamins are essential to maintaining nuclear integrity, and loss of lamin A/C results in increased cellular sensitivity to mechanical strain and defective mechanotransduction signaling. Since increased mechanical sensitivity in vascular cells could contribute to loss of smooth muscle cells and the development of arteriosclerosis -the leading cause of death in HGPS patients -we investigated the effect of mechanical stress on cells from HGPS patients. We found that skin fibroblasts from HGPS patients developed progressively stiffer nuclei with increasing passage number. Importantly, fibroblasts from HGPS patients had decreased viability and increased apoptosis under repetitive mechanical strain, as well as attenuated wound healing, and these defects preceded changes in nuclear stiffness. Treating fibroblasts with farnesyltransferase inhibitors restored nuclear stiffness in HGPS cells and accelerated the wound healing response in HGPS and healthy control cells by increasing the directional persistence of migrating cells. However, farnesyltransferase inhibitors did not improve cellular sensitivity to mechanical strain. These data suggest that increased mechanical sensitivity in HGPS cells is unrelated to changes in nuclear stiffness and that increased biomechanical sensitivity could provide a potential mechanism for the progressive loss of vascular smooth muscle cells under physiological strain in HGPS patients.

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Section: Discussionmentioning

confidence: 99%

Increased mechanosensitivity and nuclear stiffness in Hutchinson–Gilford progeria cells: effects of farnesyltransferase inhibitors

et al. 2008

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“…Atherosclerosis in HGPS seems to be related to the same mechanisms by which mutant LMNA produces accelerated aging in other tissues, such as replicative senescence, telomere shortening, decreased capacity to propagate in subculture, and decreased repair capacity. 7 Another proposed mechanism for atherosclerosis in HGPS is hyperhyaluronic acidemia and aciduria, which are suggested to cause vascular calcification.…”

Section: Discussionmentioning

confidence: 99%

Novel LMNA Mutation in Atypical Werner Syndrome Presenting With Ischemic Disease

Renard

Fourcade

Milhaud

et al. 2009

Stroke

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Background and Purpose-Laminopathies arise through mutations in genes encoding Lamin A/C (LMNA) or associated proteins. They cause 4 different groups of disorders with diverse severity and often overlapping features: diseases of striated muscle (leading to muscular or cardiac involvement), peripheral neuropathy, lipodystrophy syndromes, and accelerated aging disorders. Summary of Case-We report on a familial case of atypical Werner syndrome (a progeroid syndrome with Werner syndrome phenotype but without typical RECQL2 mutation) presenting with acute ischemic cerebral disease or peripheral artery disease associated with diffuse atherosclerosis, attributable to transmission of a novel LMNA mutation. Conclusions-In young patients with ischemic events and a positive family history, other progeroid features have to be searched and LMNA testing has to be considered, allowing for genetic counseling and presymptomatic testing of at-risk relatives. (Stroke. 2009;40:e11-e14.)

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“…Because of the shortness of the follow-up period, we do not have valuable results at present, but we will report the obtained results in the future. Mutations in LMNA have been discovered in a staggering variety of inherited diseases called "laminopathies 20) ". To date, several laminopathies are more familiar than Hutchinson-Gilford progeria syndrome (HGPS), such as Dunnigan-type familial partial lipodystrophy (FPLD), Emery-Dreifuss muscular dystrophy, Charcot-Marie-Tooth disease, limb-girdle muscular dystrophy, mandibuloacral dysplasia, dilated cardiomyopathy with conduction abnormality and early onset of atrial fibrillation.…”

Section: Discussionmentioning

confidence: 99%

A Promoter Polymorphism of Lamin A/C Gene is an Independent Genetic Predisposition to Arterial Stiffness in a Japanese General Population (The Tanno and Sobetsu Study)

Akasaka

Katsuya

Saitoh

et al. 2009

JAT

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Aim:We examined the hypothesis that there is a positive, independent association between polymorphisms of lamin A/C gene (LMNA) and arterial stiffness in Japanese. Methods: The subjects were 261 men (mean age, 64.4 0.7 years) selected from inhabitants of the towns of Tanno and Sobetsu in a rural area of Japan who underwent medical check-ups. We conducted clinical examinations, including measurement of bilateral brachial-ankle pulse wave velocity (baPWV) as a marker of arterial stiffness, and genetic analysis. Subjects with atrial fibrillation, subjects with ankle-brachial index 0.9, and subjects taking any medication were excluded. We selected two single nucleotide polymorphisms (SNPs) as markers of LMNA, 1908C/T in exon 10 and -1030C/T in the promoter region, which we have recently identified. All genotypes were clearly determined by the TaqMan PCR method. Results: Genotype frequencies of the two polymorphisms satisfied the Hardy-Weinberg equilibrium. The baPWV of -1030C/T polymorphism was significantly greater in subjects with CC genotype than in subjects with CT TT genotype (1,652 22.1 cm/s vs. 1,552 43.0 cm/s, p 0.039); however, no significant difference was found for 1908C/T polymorphism. The baPWV was found to be significantly associated with age, body height, systolic blood pressure, and smoking habit; therefore, we next performed multiple regression analysis including these parameters, and found an independent, significant association between baPWV and -1030C/T polymorphism. Conclusion: Promoter -1030C/T polymorphism of LMNA is a possible genetic predisposition to arterial stiffness in the Japanese population.

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Laminopathies and Atherosclerosis

Cited by 47 publications

References 61 publications

Increased mechanosensitivity and nuclear stiffness in Hutchinson–Gilford progeria cells: effects of farnesyltransferase inhibitors

Increased mechanosensitivity and nuclear stiffness in Hutchinson–Gilford progeria cells: effects of farnesyltransferase inhibitors

Novel LMNA Mutation in Atypical Werner Syndrome Presenting With Ischemic Disease

A Promoter Polymorphism of Lamin A/C Gene is an Independent Genetic Predisposition to Arterial Stiffness in a Japanese General Population (The Tanno and Sobetsu Study)

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