Targeting Endothelial Dysfunction in Vascular Complications Associated with Diabetes

Sharma, Arpeeta; Bernatchez, Pascal

doi:10.1155/2012/750126

Cited by 55 publications

(68 citation statements)

References 116 publications

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“…Diabetes is widely regarded as an independent risk factor for the development of cardiovascular diseases, with ;80% of cardiovascular mortality and morbidity being linked to macrovascular complications, such as atherosclerosis (1)(2)(3). The increased risk of development of vascular complications in individuals with type 1 (T1D) or type 2 diabetes (T2D) occurs despite intensive glycemic control, stressing the need for novel approaches to lessen the burden of diabetes-mediated macrovascular injury (4).…”

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confidence: 99%

Direct Endothelial Nitric Oxide Synthase Activation Provides Atheroprotection in Diabetes-Accelerated Atherosclerosis

et al. 2015

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Patients with diabetes have an increased risk of developing atherosclerosis. Endothelial dysfunction, characterized by the lowered bioavailability of endothelial NO synthase (eNOS)-derived NO, is a critical inducer of atherosclerosis. However, the protective aspect of eNOS in diabetes-associated atherosclerosis remains controversial, a likely consequence of its capacity to release both protective NO or deleterious oxygen radicals in normal and disease settings, respectively. Harnessing the atheroprotective activity of eNOS in diabetic settings remains elusive, in part due to the lack of endogenous eNOS-specific NO release activators. We have recently shown in vitro that eNOS-derived NO release can be increased by blocking its binding to Caveolin-1, the main coat protein of caveolae, using a highly specific peptide, CavNOxin. However, whether targeting eNOS using this peptide can attenuate diabetes-associated atherosclerosis is unknown. In this study, we show that CavNOxin can attenuate atherosclerotic burden by ∼84% in vivo. In contrast, mice lacking eNOS show resistance to CavNOxin treatment, indicating eNOS specificity. Mechanistically, CavNOxin lowered oxidative stress markers, inhibited the expression of proatherogenic mediators, and blocked leukocyte-endothelial interactions. These data are the first to show that endogenous eNOS activation can provide atheroprotection in diabetes and suggest that CavNOxin is a viable strategy for the development of antiatherosclerotic compounds.Diabetes is widely regarded as an independent risk factor for the development of cardiovascular diseases, with ;80% of cardiovascular mortality and morbidity being linked to macrovascular complications, such as atherosclerosis (1-3). The increased risk of development of vascular complications in individuals with type 1 (T1D) or type 2 diabetes (T2D) occurs despite intensive glycemic control, stressing the need for novel approaches to lessen the burden of diabetes-mediated macrovascular injury (4).The vascular endothelium plays a crucial role in diabetesassociated atherosclerosis through the regulation of vessel permeability, inflammation, coordination of leukocyte trafficking, and thrombosis (1,5). Indeed, the function of the vascular endothelium is significantly impaired during diabetes, a phenomena termed endothelial dysfunction and characterized by the reduced bioavailability of an important endothelial cell mediator, nitric oxide (NO). Such chronic attenuation of endothelial-derived NO release promotes platelet and leukocyte activation and adhesion, compromises endothelial cell barrier integrity, and causes the upregulation of proinflammatory genes (6-8). Moreover, reduced NO-dependent vasodilation and increased leukocyte adhesion to the endothelium, both of which are hallmarks of endothelial dysfunction, have been observed in patients with diabetes and diabetic animal models (9-12). Similarly, in cultured endothelial cells exposed to high glucose, lowered endothelial NO synthase (eNOS)-derived NO release was observed (13-15). In...

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Direct Endothelial Nitric Oxide Synthase Activation Provides Atheroprotection in Diabetes-Accelerated Atherosclerosis

et al. 2015

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“…In addition, fasudil has been able to limit TNF-alphamediated ICAM-1 expression and eNOS dephosphorylation in diabetic microvasculature [238]. Newer ROCK inhibitors with higher specificity among ROCK isoforms might represent potential therapeutic approaches to treat vascular complications associated to diabetes [239,240].…”

Section: Rock (Rho-associated Kinase) Inhibitors -mentioning

confidence: 99%

“…Anti-oxidant molecules may protect from endothelial dysfunction by re-coupling eNOS activity, reduce superoxide production, increase the activity of superoxide scavenging enzymes, or decrease vascular NAD(P)H oxidase activity [251,252]. Novel antioxidant therapies aiming to restore production of endothelialderived NO or to act as endogenous antioxidant enzymes may represent a more targeted strategy focusing specifically on the mechanisms implicated in diabetes-induced endothelial dysfunction (reviewed in [240].…”

Section: Rock (Rho-associated Kinase) Inhibitors -mentioning

confidence: 99%

Targeting endothelial metaflammation to counteract diabesity cardiovascular risk: Current and perspective therapeutic options

Potenza

Nacci

Salvia

et al. 2017

Pharmacological Research

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Abstract:The association of obesity and diabetes, termed "diabesity", defines a combination of primarily metabolic disorders with insulin resistance as the underlying common pathophysiology. Cardiovascular disorders associated with diabesity represent the leading cause of morbidity and mortality in the Western world. This makes diabesity, with its rising impacts on both health and economics, one of the most challenging biomedical and social threats of present century. The emerging comprehension of the genes whose alteration confers inter-individual differences on risk factors for diabetes or obesity, together with the potential role of genetically determined variants on mechanisms controlling responsiveness, effectiveness and safety of anti-diabetic therapy underlines the need of additional knowledge on molecular mechanisms involved in the pathophysiology of diabesity. Endothelial cell dysfunction, resulting from the unbalanced production of endothelialderived vascular mediators, is known to be present at the earliest stages of insulin resistance and obesity, and may precede the clinical diagnosis of diabetes by several years. Once considered as a mere consequence of metabolic abnormalities, it is now clear that endothelial dysfunctional activity may play a pivotal role in the progression of diabesity. In the vicious circle where vascular defects and metabolic disturbances worsen and reinforce each other, a low-grade, chronic, and 'cold' inflammation (metaflammation) has been suggested to serve as the pathophysiological link that binds endothelial and metabolic dysfunctions. In this paradigm, it is important to consider how traditional antidiabetic treatments (specifically addressing metabolic dysregulation) may directly impact on inflammatory processes or cardiovascular function. Indeed, not all drugs currently available to treat diabetes possess the same anti-inflammatory potential, or target endothelial cell function equally. Perspective strategies pointing at reducing metaflammation or directly addressing endothelial dysfunction may disclose beneficial consequences on metabolic regulation. This review focuses on existing and potential new approaches ameliorating endothelial dysfunction and vascular inflammation in the context of diabesity.

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“…Az L-arginin-szupplementáció ésszerű módszer az endothel NO-termelésének növelésére és a szabad gyökök képződésének csökkentésére; a cGMP-termelés fokozása révén helyreállítja az endotheldependens értágulást [72]. Az étrend kiegészítése 7 g/nap argininnal visszafordítja az endothel funkciózavarát, és javulást eredményez sok érrendellenességben [73].…”

Section: L-arginin-szupplementációunclassified

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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Targeting Endothelial Dysfunction in Vascular Complications Associated with Diabetes

Cited by 55 publications

References 116 publications

Direct Endothelial Nitric Oxide Synthase Activation Provides Atheroprotection in Diabetes-Accelerated Atherosclerosis

Direct Endothelial Nitric Oxide Synthase Activation Provides Atheroprotection in Diabetes-Accelerated Atherosclerosis

Targeting endothelial metaflammation to counteract diabesity cardiovascular risk: Current and perspective therapeutic options

Adalékok az időskori maculadegeneráció – etiopatogeneziséből fakadó – gyógyszeres intervenciójához

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