Advanced glycation endproduct crosslink breaker (alagebrium) improves endothelial function in patients with isolated systolic hypertension

Zieman, Susan J.; Melenovský, Vojtěch; Clattenburg, Lia; Corretti, Mary C.; Capriotti, Anne; Gerstenblith, Gary; Kass, David A.

doi:10.1097/hjh.0b013e328013e7dd

Cited by 181 publications

(138 citation statements)

References 48 publications

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“…Furthermore, administration of AGE crosslink breaker (ALT-711) to patients with hypertension was associated with a concurrent reduction in AGEs, improved endothelial function and reduced arterial stiffness and pulse pressure [29]. These data bolster the evidence of the involvement of AGEs in hypertension as well as arterial stiffening [29,[59][60][61]. We showed for the first time that higher circulating levels of CML were associated with lower diastolic blood pressure and higher pulse pressure in young healthy normotensive individuals.…”

Section: Discussionsupporting

confidence: 66%

Plasma advanced glycation end products (AGEs) and NF-κB activity are independent determinants of diastolic and pulse pressure

Sourris

Lyons

Dougherty

et al. 2014

Clinical Chemistry and Laboratory Medicine

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Background: High levels of circulating advanced glycation end products (AGEs) can initiate chronic low-grade activation of the immune system (CLAIS) with each of these factors independently associated with cardiovascular (CV) morbidity and mortality. Therefore, our objective was to characterize the relationship between serum AGEs, CLAIS and other risk factors for CV disease in normotensive non-diabetic individuals. Methods: We measured body mass index (BMI), waistto-hip ratio (WHR), blood pressure, lipid and glucose profile in 44 non-diabetic volunteers (17 female, 27 males). Carbo xymethyl-lysine (CML) was measured by ELISA as a marker for circulating AGEs and NF-κB p65 activity as an inflammatory marker by DNA-binding in peripheral blood mononuclear cells lysates (PBMC). Results: Plasma CML concentrations were related to diastolic blood pressure (r = −0.51, p < 0.01) independently of age, sex, BMI and WHR (p < 0.05). Diastolic blood pressure was also related to NF-κB activity in PBMC (r = 0.47, p < 0.01) before and after adjustment for age, sex, BMI and WHR (p < 0.05). Plasma CML concentrations were related to the pulse pressure before (r = 0.42; p < 0.05) and after adjustment for age, sex, BMI and waist (p < 0.05). Neither CML nor NF-κB activity were related to systolic blood pressure (both p = ns). Plasma CML concentrations were not associated with plasma lipid or glucose concentrations (all p = ns). Conclusions: Plasma AGE levels and NF-κB activity in PBMC were independent determinants of diastolic and pulse pressure in healthy normotensive individuals. This association suggests a role for AGEs in the etiology of hypertension, possibly via the initiation of CLAIS and aortic stiffening.

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Section: Discussionsupporting

confidence: 66%

Plasma advanced glycation end products (AGEs) and NF-κB activity are independent determinants of diastolic and pulse pressure

Sourris

Lyons

Dougherty

et al. 2014

Clinical Chemistry and Laboratory Medicine

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“…The prevention or decrease of glycation and glycation-induced tissue damage could be possible therapeutic strategies for the treatment of diabetic neuropathy [39,40]. Recent clinical studies have shown that AGE breakers, including ALT-711 and alagebrium, may be able to decrease the adverse vascular effects of glycation with few side effects [41][42][43], although no benefits have been demonstrated in the area of neuropathy. The inhibition of pathological responses mediated by AGEs may have therapeutic potential for diabetic neuropathy, although the RAGE-mediated molecular mechanisms need to be explored in further studies.…”

Section: Discussionmentioning

confidence: 99%

Advanced glycation end-products induce basement membrane hypertrophy in endoneurial microvessels and disrupt the blood–nerve barrier by stimulating the release of TGF-β and vascular endothelial growth factor (VEGF) by pericytes

et al. 2011

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Aims/hypothesis The breakdown of the blood-nerve barrier (BNB) is considered to be a key step in diabetic neuropathy. Although basement membrane hypertrophy and breakdown of the BNB are characteristic features of diabetic neuropathy, the underlying pathogenesis remains unclear. The purpose of the present study was to identify the possible mechanisms responsible for inducing the hypertrophy of basement membrane and the disruption of the BNB after exposure to AGEs. Methods The newly established human peripheral nerve microvascular endothelial cell (PnMEC) and pericyte cell lines were used to elucidate which cell types constituting the BNB regulate the basement membrane and to investigate the effect of AGEs on the basement membrane of the BNB using western blot analysis. Results Fibronectin, collagen type IV and tissue inhibitor of metalloproteinase (TIMP-1) protein were produced mainly by peripheral nerve pericytes, indicating that the basement membrane of the BNB is regulated mainly by these cells. AGEs reduced the production of claudin-5 in PnMECs by increasing autocrine signalling through vascular endothelial growth factor (VEGF) secreted by the PnMECs themselves.Furthermore, AGEs increased the amount of fibronectin, collagen type IV and TIMP-1 in pericytes through a similar upregulation of autocrine VEGF and transforming growth factor (TGF)-β released by pericytes. Conclusions/interpretation These results indicate that pericytes may be the main regulators of the basement membrane at the BNB. AGEs induce basement membrane hypertrophy and disrupt the BNB by increasing autocrine VEGF and TGF-β signalling by pericytes under diabetic conditions.

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“…Az AGE keresztkötése-it törő alagebrium fokozza a perifériás artériák endotheljének a működését, mérsékeli az ED-t [69], a teljes impedanciát javítja, valamint csökkenti a centrális artériák merevségét és az erek átépülését.…”

Section: Alagebriumunclassified

Adalékok az időskori maculadegeneráció – etiopatogeneziséből fakadó – gyógyszeres intervenciójához

Fischer¹

2015

Orvosi Hetilap

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"A jelenségek közötti kapcsolatok új értelmezése, különösen, ha intellektuális értéket teremt, ér annyit, mint egy felfedezés."A szem struktúráit vérrel ellátó érendothelium működészavarának kulcsfontosságú szerepe van az időskori maculadegeneráció létrejöttében. Az időskori maculadegeneráció érbetegség, végső soron az egész érrendszer megbetegedé-sének a része. Az endotheldiszfunkció helyreállítása megakadályozza az érbántalom és így az időskori maculadegeneráció kialakulását, vagy csökkenti a már kialakult elváltozást. A kockázati tényezők jelenlétében kialakuló endotheldiszfunkció és következményes időskori maculadegeneráció kiküszöbölésére, megelőzésére, illetve kezelésé-re nem gyógyszeres és gyógyszeres lehetőségek állnak rendelkezésre. Jelen dolgozat a gyógyszeres intervenciót taglalja. Ezek közé tartoznak a renin-angiotenzin rendszert gátló angiotenzinkonvertálóenzim-gátlók, angiotenzinreceptor-blokkolók és renininhibitorok, statinok, acetilszalicilsav, trimetazidin, harmadik generációs béta-blokkolók, peroxiszómaproliferátor-aktivált receptor-gamma-agonisták, folsav, D-vitamin, melatonin, az előrehaladt glikációs végtermékek keresztkötéseit feltörő alagebrium, az endothelinreceptor-antagonista bosentan, koenzim Q 10 , "kauzá-lis" antioxidáns vitaminok, rezveratrol, L-arginin, szerotoninreceptor-agonisták, tumornekrózis-faktor-alfa-blokkolók, a komplement alternatív útjának specifi kus gátlója, kurkumin és a doxiciklin. Az endothel működésének helyreállítása stabilizálja az állapotot idült érbetegségek, így időskori maculadegeneráció esetében is. Az emberi érrendszer egylényegűségét is tekintetbe véve a megelőzésre a felsorolt gyógyszereket azoknak a betegeknek kell adni, (1) akiknek nincs maculadegenerációja, de fennállnak az időskori maculadegeneráció endothelműködés-zavart kiváltó kockázati tényezői és 50 évesnél idősebbek, (2) akiknél egyoldali időskori maculadegenerációt állapítottak meg, a másik szem károsodásának a megelőzésére, valamint (3) kétoldali időskori maculadegenerációban szenvedőknek a romlás kivédésére és az esetleges javulás reményében. Mindezekhez randomizált prospektív klinikai vizsgálatok szük-ségesek. Orv. Hetil., 2015, 156(46), 1847-1858.Kulcsszavak: időskori maculadegeneráció, endotheldiszfunkció, oxidatív stressz, kockázati tényező, prevenció, élet-mód megváltoztatása, nem gyógyszeres terápia, gyógyszeres terápia Pharmacological therapy of age-related macular degeneration based on the etiopathogenesisIt is of great therapeutic signifi cance that disordered function of the vascular endothelium which supply the affected ocular structures plays a major role in the pathogenesis and development of age-related macular degeneration. Chronic infl ammation is closely linked to diseases associated with endothelial dysfunction, and age-related macular degeneration is accompanied by a general infl ammatory response. According to current concept, age-related macular degeneration is a local manifestation of systemic vascular disease. This recognition could have therapeutic implications because...

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Advanced glycation endproduct crosslink breaker (alagebrium) improves endothelial function in patients with isolated systolic hypertension

Cited by 181 publications

References 48 publications

Plasma advanced glycation end products (AGEs) and NF-κB activity are independent determinants of diastolic and pulse pressure

Plasma advanced glycation end products (AGEs) and NF-κB activity are independent determinants of diastolic and pulse pressure

Advanced glycation end-products induce basement membrane hypertrophy in endoneurial microvessels and disrupt the blood–nerve barrier by stimulating the release of TGF-β and vascular endothelial growth factor (VEGF) by pericytes

Adalékok az időskori maculadegeneráció – etiopatogeneziséből fakadó – gyógyszeres intervenciójához

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