Hyperhomocysteinemia-Induced Vascular Damage in the Minipig

Rolland, Pierre H.; Friggi, A; Barlatier, A; Piquet, Philippe; Latrille, Valérie; Faye, Marie M.; Guillou, J.; Charpiot, Philippe; Bodard, H.; Ghiringhelli, Odette; Calaf, R; Luccioni, R; Garçon, Danielle

doi:10.1161/01.cir.91.4.1161

Cited by 196 publications

(84 citation statements)

References 51 publications

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“…Normally aged skin that has not been chronically exposed to sunlight is characterized by generalized wrinkling, an epidermal layer thickened by regions of hyperkeratosis, thinning of the underlying dermis (Tyner et al, 2002). The alterations of the architecture of the collagen and elastin networks are common features in aging tissues such as skin (Lavker et al, 1986) and arteries (Rosenthal, 1987) and were also observed in arterial tree of a dietary model of hyperhomocysteinemia in minipig (Rolland et al, 1995) and in cerebral arterioles of CBS-deficient mice (Baumbach et al, 2002).…”

Section: Resultsmentioning

confidence: 97%

Hyperkeratosis in cystathionine beta synthase‐deficient mice: An animal model of hyperhomocysteinemia

et al. 2004

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Cystathionine beta synthase (CBS) is a crucial regulator of plasma concentrations of homocysteine. Severe hyperhomocysteinemia due to CBS deficiency confers diverse clinical manifestations. Patients with severe hyperhomocysteinemia have fine hair and thin skin, but it is unclear whether these changes are related to CBS deficiency or are coincidental. To investigate these aspects of hyperhomocysteinemia, we characterized skin abnormalities of CBS-deficient mice, a murine model of severe hyperhomocysteinemia. Histological and histomorphometric analyses revealed that CBS-deficient mice have wrinkled skin with hyperkeratinosis of the epidermis and thinning of the dermis.

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Section: Resultsmentioning

confidence: 97%

Hyperkeratosis in cystathionine beta synthase‐deficient mice: An animal model of hyperhomocysteinemia

et al. 2004

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“…Moreover, macrophage-driven foam cell formation might be increased by the interaction between homocysteine thiolactone and LDL (McCully, 1996;Olszewski and McCully, 1993). Along with the direct activation of matrix metalloproteinase-2 (Bescond et al, 1999), vascular damage might also result from an impairment of the tertiary structure of connective tissue protein, because of the reduced degree of cross-linkage between collagen and fibrin monomers (Lubec et al, 1996a;McCully, 1996;Rolland et al, 1995). A defect in collagen polymerization was reported in homocystinuric patients with severe hyperhomocysteinemia (Lubec et al, 1996a).…”

Section: Hyperhomocysteinemia-mediated Oxidant Stress Through Imbalanmentioning

confidence: 99%

“…Although additional studies are required to clarify the molecular mechanisms responsible for hyperhomocysteinemiainduced vascular disorders, there is evidence that the direct cytotoxicity of markedly elevated homocysteine and/or of its oxidized by-products (homocysteine thiolactone, homocysteine sulfinic acid, and homocysteic acid) damages endothelial cells (Dudman et al, 1991;Starkebaum and Harlan, 1986;Wall et al, 1980). This direct cytotoxicity may also cause alteration in the tertiary structure of proteins in connective tissue and hence affect the vascular wall structure (Lubec et al, 1996a;McCully, 1996;Rolland et al, 1995). Specific disulfide linkage between homocysteine and the sulfhydryl group of an intracellular protein may be an alternative molecular mechanism underlying hyperhomocysteinemia-induced vascular dysfunction.…”

Section: Durand Et Almentioning

confidence: 99%

Impaired Homocysteine Metabolism and Atherothrombotic Disease

Durand

Prost²,

Loreau

et al. 2001

Laboratory Investigation

232

147

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SUMMARY:Based on recent retrospective, prospective, and experimental studies, mild to moderate elevation of fasting or postmethionine-load plasma homocysteine is accepted as an independent risk factor for cardiovascular disease and thrombosis in both men and women. Hyperhomocysteinemia results from an inhibition of the remethylation pathway or from an inhibition or a saturation of the transsulfuration pathway of homocysteine metabolism. The involvement of a high dietary intake of methionine-rich animal proteins has not yet been investigated and cannot be ruled out. However, folate deficiency, either associated or not associated with the thermolabile mutation of the N 5,10 -methylenetetrahydrofolate reductase, and vitamin B 6 deficiency, perhaps associated with cystathionine ␤-synthase defects or with methionine excess, are believed to be major determinants of the increased risk of cardiovascular disease related to hyperhomocysteinemia. Recent experimental studies have suggested that moderately elevated homocysteine levels are a causal risk factor for atherothrombotic disease because they affect both the vascular wall structure and the blood coagulation system. The oxidant stress that results from impaired homocysteine metabolism, which modifies the intracellular redox status, might play a central role in the molecular mechanisms underlying moderate hyperhomocysteinemia-mediated vascular disorders. Because folate supplementation can efficiently reduce plasma homocysteine levels, both in the fasting state and after methionine loading, results from further prospective cohort studies and from on-going interventional trials will determine whether homocysteine-lowering therapies can contribute to the prevention and reduction of cardiovascular risk. Additionally, these studies will provide unequivocal arguments for the independent and causal relationship between hyperhomocysteinemia and atherothrombotic disease. (Lab Invest 2001, 81:645-672).C ardiovascular diseases remain the leading cause of mortality in Western populations. Hyperlipoproteinemia, hypertension, diabetes, obesity, and tobacco smoking are the main risk factors for atherosclerosis and its thrombotic complications. However, these factors alone cannot account for all of the deaths caused by vascular pathologies.As early as 1969, clinical studies conducted in homocystinuric children revealed the importance of severe hyperhomocysteinemia in premature development of atherosclerosis and thromboembolism (McCully, 1983). According to numerous retrospective case-controlled studies, moderate increases in plasma homocysteine, which can be precisely quantitated by high performance liquid chromatography (HPLC), raise the risk for cardiovascular disease 2-fold, after adjusting for classic risk factors. Moreover, up to 20% to 40% of patients with vascular pathologies present moderate to intermediate hyperhomocysteinemia. However, results from prospective studies are inconsistent. Additionally, molecular mechanisms underlying hyperhomocysteinemia-induced vascular diseas...

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“…A study in pigs showed that a high methionine diet which produces high serum homocysteine produced elevated PAH [141]. e lung dysfunction in this last study [141] was greatly lowered by an angiotensin-converting enzyme inhibitor, strongly suggesting a role for excessive superoxide in homocysteine-initiated PAH as well.…”

Section: Principlementioning

confidence: 55%

Pulmonary Hypertension Is a Probable NO/ONOO⁻Cycle Disease: A Review

Pall

2013

ISRN Hypertension

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e NO/ONOO − cycle is a primarily local biochemical/physiological vicious cycle that appears to cause a series of chronic in�ammatory diseases. is paper focuses on whether the cycle causes pulmonary arterial hypertension (PAH) when located in the pulmonary arteries. e cycle involves 12 elements, including superoxide, peroxynitrite (ONOO − ), nitric oxide (NO), oxidative stress, NF-B, in�ammatory cytokines, iNOS, mitochondrial dysfunction, intracellular calcium, tetrahydrobiopterin depletion, NMDA activity, and TRP receptor activity. 10 of the 12 are elevated in PAH (NMDA?, NO?) and 11 have documented causal roles in PAH. Each stressor that initiates cases of PAH acts to raise cycle elements, and may, therefore, initiate the cycle in this way. PAH involves a primarily local mechanism as required by the cycle and the symptoms and signs of PAH are generated by elements of the cycle. Endothelin-1, which acts as a causal factor in PAH, acts as part of the cycle; its synthesis is stimulated by cycle elements, and it, in turn, increases each element of the cycle. is extraordinary �t to the principles of the NO/ONOO − cycle allows one to conclude that PAH is a NO/ONOO − cycle disease, and this �t supports the cycle as a ma�or paradigm of chronic in�ammatory disease.

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Hyperhomocysteinemia-Induced Vascular Damage in the Minipig

Cited by 196 publications

References 51 publications

Hyperkeratosis in cystathionine beta synthase‐deficient mice: An animal model of hyperhomocysteinemia

Hyperkeratosis in cystathionine beta synthase‐deficient mice: An animal model of hyperhomocysteinemia

Impaired Homocysteine Metabolism and Atherothrombotic Disease

Pulmonary Hypertension Is a Probable NO/ONOO⁻Cycle Disease: A Review

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Hyperhomocysteinemia-Induced Vascular Damage in the Minipig

Cited by 196 publications

References 51 publications

Hyperkeratosis in cystathionine beta synthase‐deficient mice: An animal model of hyperhomocysteinemia

Hyperkeratosis in cystathionine beta synthase‐deficient mice: An animal model of hyperhomocysteinemia

Impaired Homocysteine Metabolism and Atherothrombotic Disease

Pulmonary Hypertension Is a Probable NO/ONOO−Cycle Disease: A Review

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Product

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Pulmonary Hypertension Is a Probable NO/ONOO⁻Cycle Disease: A Review