Endothelial cell dysfunction in type I and II diabetes: The cellular basis for dysfunction

Abstract

Micro-and macrovascular complications are the leading causes of mortality in Types I and II diabetes. Hyperglycemia results in increased advanced glycosylation end (AGE) products, oxidative stress, increased sorbitol levels, and increased activation of protein kinase C. These effects of hyperglycemia eventually lead to impaired endothelium-dependent relaxation to vasoactive substances such as acetylcholine and bradykinin. Increased oxidative stress, which will reduce levels of nitric oxide (NO), and/or decreased bioavailability of tetrahydrobiopterin (BH 4 ), a cofactor for endothelial NO synthase (eNOS), may lead to a phenomenon called ''uncoupling'' of eNOS and this leads to endothelial dysfunction. Uncoupled NOS produces superoxide anions which lead to a further reduction in NO bioavailability. Thus, restoring BH4 levels and antioxidant activity could prove to be novel approaches for the treatment of endothelial dysfunction in Type I and II diabetes. Drug Dev. Res. 58:28-41, 2003.

Endothelial dysfunction in Type 2 diabetes correlates with deregulated expression of the tail-anchored membrane protein SLMAP

“…Experimental protocols. Vascular smooth muscle reactivity to phenylephrine (PE) and endothelium-dependent relaxation to acetylcholine (ACh) were studied using a Mulvany-Halpern myograph as previously described (27,28,29,30,31). After a 45-min equilibration period, the vascular reactivity to PE was studied in second-order small mesenteric arteries (SMAs) from db/ϩ and db/db mice.…”

“…The cardiovascular complications and specifically the linkage to endothelial dysfunction that are seen at an early stage in patients with diabetes are considered as the major risk factor for both Type 1 and Types 2 diabetes (9,12,13,29,(37)(38)(39). The etiology of Type 2 diabetes is complex and involves both genetic predisposition as well as environmental factors, notably, lifestyle and dietary influences.…”

Twenty-five years since the discovery of endothelium-derived relaxing factor (EDRF): does a dysfunctional endothelium contribute to the development of type 2 diabetes?

“…Patients suffering from type 2 diabetes have a high risk of ED, which occurs from early stage in diabetes and is a hallmark of diabetic vascular disease; this subject has been extensively reviewed (Cosentino and Lüscher 1998;De Vriese et al 2000;Pannirselvam et al 2003). Hyperglycaemia, insulin resistance, dyslipidemia, hypertension, and advanced glycation end products have all been suggested to contribute to the development of ED and vascular pathologies (Cosentino and Lüscher 1998;Creager et al 2003;De Vriese et al 2000;Pannirselvam et al 2003) with the majority view that ED and vascular disease occur secondarily to the development of insulin resistance and the resultant decrease in the disposal of glucose and hyperglycaemia.…”

“…Thus, endothelial dysfunction (ED) has come to be defined as a reduced endothelium-dependent vasodilator response to acetylcholine. 3 Although the endothelium plays many additional functions on vascular homeostasis beyond the control of vascular tone, this reduced response to acetylcholine serves as an important indicator and assay of vascular dysfunction (Andrews et al 2005;De Vriese et al 2000;Pannirselvam et al 2003;Triggle et al 2003). In the past 25 years, other significant advancements have been made in the diagnosis and management of vascular diseases but it was the discovery of the importance of endogenously generated NO that tops the list (Olin et al 2004).…”

How to Control NO Production in Cells: Nω,Nω‐Dimethyl‐L‐Arginine Dimethylaminohydrolase as a Novel Drug Target

“…[42,43] Scheme 1 presents an overview about the metabolism of ADMA, which appears iñ tenfold higher concentration compared to MMA. [44] [22] bone iNOS asthma [111] lung iNOS diabetes [112] cardiovascular eNOS inflammation [113] various eNOS (acute), iNOS (chronic) ischemia [114] brain, heart iNOS, nNOS meningitis [115] brain iNOS migraine [25] brain iNOS neurodegeneration [a], [116] brain iNOS, nNOS septic shock [26] various iNOS stroke (cerebral ischemia) [117] brain nNOS, iNOS Like MMA, ADMA is a competitive inhibitor of NOS, whereas SDMA is not. [45] A strong indication that NO production depends on MMA and ADMA also in vivo was given through a number of cell culture and tissue studies, [46][47][48] injection of MMA into human volunteers, [49] and through experiments with transgenic mice.…”