Losartan, an angiotensin type 1 receptor antagonist, improves endothelial function in non-insulin-dependent diabetes

Cheetham, Craig; Collis, Julie; O’Driscoll, Gerry; Stanton, K.; Taylor, Roger R.; Green, Daniel

doi:10.1016/s0735-1097(00)00933-5

Cited by 119 publications

(97 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Under diabetic conditions, the renin-Ang system is activated and vascular AT1R expression is enhanced, 11,22 thereby contributing to diabetes mellitus-associated endothelial dysfunction. 12 Given the known vascular (endothelial)-protective effects of HDL, [13][14][15] we hypothesized that HDL could also regulate vascular AT1R expression under diabetic conditions and could thereby influence Ang II-mediated signaling. To investigate this hypothesis, we increased HDL in vivo via human apo A-I gene transfer, leading to hepatocyte-specific human apo A-I expression in STZ-induced diabetic rats and supplemented HDL to HAECs under HG in the presence or absence of Ang II.…”

Section: Discussionmentioning

confidence: 99%

“…In brief, diabetes mellitus was induced by a single injection of streptozotocin (STZ; 70 mg/kg; IP) in 8-week-old male Sprague-Dawley (SD) rats. Five days after STZ injection, IV gene transfer with 3ϫ10 12 particles per kg of the E1E3E4-deleted adenoviral vector Ad.hapo A-I, which induces hepatocyte-specific expression of human apo A-I in the absence of significant hepatotoxicity, 21 or of the control vector Ad.Null, which contains no expression cassette, 21 was performed. Six weeks after gene transfer, rats were euthanized, and endothelium-dependent vasorelaxation was determined.…”

Section: Methodsmentioning

confidence: 99%

“…10,11 The importance of the enhanced vascular AT1R expression and Ang II-mediated signaling in diabetes mellitus-associated endothelial dysfunction follows from the finding that AT1R antagonism in diabetes mellitus improves endothelial function. 7,12 The vascular protective effects of high-density lipoprotein (HDL) are well documented: low plasma HDL is an independent predictor of endothelial dysfunction in healthy individuals and diabetic patients, 13,14 and elevation of plasma HDL by drug treatment with niacin or by infusion of synthetic HDL leads to a significant improvement of impaired endothelial function. 15 Recently, HDL-mediated reduction in NOX activity has been demonstrated.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Vascular-Protective Effects of High-Density Lipoprotein Include the Downregulation of the Angiotensin II Type 1 Receptor

et al. 2009

View full text Add to dashboard Cite

Abstract-There is growing evidence that a cross-talk exists between the renin-angiotensin (Ang) system and lipoproteins.We investigated the role of high-density lipoprotein (HDL) on Ang II type 1 receptor (AT1R) regulation and subsequent Ang II-mediated signaling under diabetic conditions. To investigate the effect of HDL on AT1R expression in vivo, apolipoprotein A-I gene transfer was performed 5 days after streptozotocin injection. Six weeks after apolipoprotein A-I gene transfer, the 1.9-fold (Pϭ0.001) increase of HDL cholesterol was associated with a 4.7-fold (PϽ0.05) reduction in diabetes mellitus-induced aortic AT1R expression. Concomitantly, NAD(P)H oxidase activity, Nox 4, and p22 phox mRNA expression were reduced 2.6-fold, 2.0-fold, and 1.5-fold (PϽ0.05), respectively, whereas endothelial NO synthase dimerization was increased 3.3-fold (PϽ0.005). Apolipoprotein A-I transfer improved NO bioavailability as indicated by ameliorated acetylcholine-dependent vasodilation in the streptozotocin-Ad.hapoA-I group compared with streptozotocin-induced diabetes mellitus. In vitro, HDL reduced the hyperglycemia-induced upregulation of the AT1R in human aortic endothelial cells. This was associated with a 1.3-fold and 2.2-fold decreases in reactive oxygen species and NAD(P)H oxidase activity, respectively (PϽ0.05). Finally, HDL reduced the responsiveness to Ang II, as indicated by decreased oxidative stress in the hyperglycemiaϩHDLϩAng II group compared with the hyperglycemiaϩAng II group. In conclusion, vascular-protective effects of HDL include the downregulation of the AT1R. Diabetes mellitus is associated with endothelial dysfunction, an early phase of atherosclerosis further characterized by a reduction in NO bioavailability, without significant morphological changes of the vessel wall. 1,2 Both diabetes mellitus-associated hyperglycemia and increased angiotensin (Ang) II levels 3 induce reactive oxygen species (ROS), which contribute to endothelial dysfunction, partly via oxidative degradation of NO. Recent studies have demonstrated that ROS are predominantly produced by vascular NAD(P)H oxidase (NOX), 4 whereas "uncoupled" endothelial NO synthase (eNOS; when eNOS produces O 2 ⅐Ϫ rather then NO) is another important source of ROS in diseased, including diabetic, blood vessels. 5 Numerous studies have shown that activation of the Ang II type 1 receptor (AT1R) contributes to the induction of oxidative stress and apoptosis of vascular cells, thus contributing to the initiation and progression of endothelial dysfunction. 6 Ang II not only increases NOX activity but also uncouples eNOS in diabetic mice. 7 The expression levels of the AT1R define the biological efficacy of Ang II and have been shown to be regulated by several agonists, such as Ang II, glucose, insulin, ROS, low-density lipoprotein (LDL), and many others, 8,9 including diabetes mellitus. 10,11 The importance of the enhanced vascular AT1R expression and Ang II-mediated signaling in diabetes mellitus-associated endothelial dysfunction follows from the ...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Vascular-Protective Effects of High-Density Lipoprotein Include the Downregulation of the Angiotensin II Type 1 Receptor

et al. 2009

View full text Add to dashboard Cite

show abstract

“…More intriguingly, the combined chronic treatment with enalapril and losartan increased ACh-induced as well as basal plasma NO concentration significantly more than either enalapril or losartan alone. Several clinical studies have demonstrated that both ACEIs and ARBs improve endothelial function in patients with cardiovascular risk factors or coronary disease (10)(11)(12). However, in those studies endothelial function was quantified by measuring secondary effects of NO, such as biologically inactive products of NO (nitrite and nitrate) or flow-dependent endothelium-mediated vasodilation.…”

Section: Discussionmentioning

confidence: 99%

“…In several clinical studies, both angiotensin-converting enzyme (ACE) inhibitors (ACEIs) and angiotensin type 1 (AT1) receptor blockers (ARBs) have been shown to improve endothelial function in patients with cardiovascular risk factors or coronary disease (10)(11)(12). However, the effects of these agents on the bioavailability of NO and vascular remodeling has not been investigated in details.…”

Section: Introductionmentioning

confidence: 99%