Endothelial Dysfunction: The Common Consequence in Diabetes and Hypertension

Institute of Vascular Medicine, Li Ka Shing Institute of Health Sciences, and School of Biomedical Sciences, Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR, China.
Journal of cardiovascular pharmacology (Impact Factor: 2.14). 04/2010; 55(4):300-7. DOI: 10.1097/FJC.0b013e3181d7671c
Source: PubMed


Endothelial dysfunction plays a key role in the initiation of cellular events evolving into the development of vascular complications in diabetes and hypertension. Diminished production and function of endothelium-derived nitric oxide and other vasoprotective factors and/or the exaggerated production of proinflammatory and vasoconstrictors such as angiotensin II, endothelin-1, reactive oxygen species, and cyclooxygenase-derived metabolites of arachidonic acid eventually lead to endothelial dysfunction, resulting in elevated vascular tone which contributes to hypertension, vascular, and cardiac remodeling, culminating in microvascular, macrovascular, and renal damages. Specific therapies targeting reactive oxygen species using antioxidants and inhibitors of the rennin-angiotensin system or increasing endothelial nitric oxide synthase activity might assist to reverse endothelial dysfunction and thus reduce the related cardiovascular morbidity and mortality in diabetes and hypertension.

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    • "Clinical efforts are based on glycemic control. The research focus of some prevention efforts is the endothelium and its role in protecting blood vessels (Fioretto et al., 2010; Wong et al., 2010). Vascular smooth muscle abnormalities, platelet dysfunction, abnormal coagulation and impaired vascular repair are other pathologies proposed to lead to diabetic vasculopathy (Beckman et al., 2002; Cubbon et al., 2013). "
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    ABSTRACT: Strategies to prevent diabetic microvascular angiopathy focus on the vascular endothelium. Because red blood cells (RBCs) are less deformable in diabetes, we explored an original concept linking decreased RBC deformability to RBC ascorbate and hyperglycemia. We characterized ascorbate concentrations from human and mouse RBCs and plasma, and showed an inverse relationship between RBC ascorbate concentrations and deformability, measured by osmotic fragility. RBCs from ascorbate deficient mice were osmotically sensitive, appeared as spherocytes, and had decreased β-spectrin. These aberrancies reversed with ascorbate repletion in vivo. Under physiologic conditions, only ascorbate's oxidation product dehydroascorbic acid (DHA), a substrate for facilitated glucose transporters, was transported into mouse and human RBCs, with immediate intracellular reduction to ascorbate. In vitro, glucose inhibited entry of physiologic concentrations of dehydroascorbic acid into mouse and human RBCs. In vivo, plasma glucose concentrations in normal and diabetic mice and humans were inversely related to respective RBC ascorbate concentrations, as was osmotic fragility. Human RBC β-spectrin declined as diabetes worsened. Taken together, hyperglycemia in diabetes produced lower RBC ascorbate with increased RBC rigidity, a candidate to drive microvascular angiopathy. Because glucose transporter expression, DHA transport, and its inhibition by glucose differed for mouse versus human RBCs, human experimentation is indicated.
    10/2015; DOI:10.1016/j.ebiom.2015.09.049
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    • "Endothelium is the major part of the vasculature in regulating vascular function. In the context of T2DM, chronic stimulation of hyperglycemia activates clusters of intrinsic vaso-regulating systems or pathways in vascular endothelium [16]. Understanding the dynamic underlying mechanisms is critical for understanding the diabetes-associated vascular dysfunction so that preventive strategies can be developed. "
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    ABSTRACT: Abstract The endothelium performs a crucial role in maintaining vascular integrity leading to whole organ metabolic homeostasis. Endothelial dysfunction represents a key etiological factor leading to moderate to severe vasculopathies observed in both Type 2 diabetic and Alzheimer's Disease (AD) patients. Accordingly, evidence-based epidemiological factors support a compelling hypothesis stating that metabolic rundown encountered in Type 2 diabetes engenders severe cerebral vascular insufficiencies that are causally linked to long term neural degenerative processes in AD. Of mechanistic importance, Type 2 diabetes engenders an immunologically mediated chronic pro-inflammatory state involving interactive deleterious effects of leukocyte-derived cytokines and endothelial-derived chemotactic agents leading to vascular and whole organ dysfunction. The long term negative consequences of vascular pro-inflammatory processes on the integrity of CNS basal forebrain neuronal populations mediating complex cognitive functions establish a striking temporal comorbidity of AD with Type 2 diabetes. Extensive biomedical evidence supports the pivotal multi-functional role of constitutive nitric oxide (NO) production and release as a critical vasodilatory, anti-inflammatory, and anti-oxidant, mechanism within the vascular endothelium. Within this context, we currently review the functional contributions of dysregulated endothelial NO expression to the etiology and persistence of Type 2 diabetes-related and co morbid AD-related vasculopathies. Additionally, we provide up-to-date perspectives on critical areas of AD research with special reference to common NO-related etiological factors linking Type 2 diabetes to the pathogenesis of AD.
    08/2014; 20:118-29. DOI:10.12659/MSMBR.891278
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    • "NO, derived from the action of eNOS in endothelial cells, is one of the most important mediators in the regulation of endothelial functions [56]. Phosphorylation of eNOS at ser1177 activates eNOS, while increased oxidative flux directly scavenges NO to lower NO bioavailability [57] and subsequently impairs endothelium-dependent vasodilatation [58]. Interestingly, as shown in many previous studies, H2O2 directly upregulated the levels of NO in endothelial cells, suggesting that overproduction of NO by endothelial cells in response to H2O2 stimulation was intended to protect the cells, rather than damage cells [59, 60]. "
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    ABSTRACT: Salidroside (SAL) is an active component of Rhodiola rosea with documented antioxidative properties. The purpose of this study is to explore the mechanism of the protective effect of SAL on hydrogen peroxide- (H2O2-) induced endothelial dysfunction. Pretreatment of the human umbilical vein endothelial cells (HUVECs) with SAL significantly reduced the cytotoxicity brought by H2O2. Functional studies on the rat aortas found that SAL rescued the endothelium-dependent relaxation and reduced superoxide anion (O2(∙-)) production induced by H2O2. Meanwhile, SAL pretreatment inhibited H2O2-induced nitric oxide (NO) production. The underlying mechanisms involve the inhibition of H2O2-induced activation of endothelial nitric oxide synthase (eNOS), adenosine monophosphate-activated protein kinase (AMPK), and Akt, as well as the redox sensitive transcription factor, NF-kappa B (NF- κ B). SAL also increased mitochondrial mass and upregulated the mitochondrial biogenesis factors, peroxisome proliferator-activated receptor gamma-coactivator-1alpha (PGC-1 α ), and mitochondrial transcription factor A (TFAM) in the endothelial cells. H2O2-induced mitochondrial dysfunction, as demonstrated by reduced mitochondrial membrane potential (Δ ψ m) and ATP production, was rescued by SAL pretreatment. Taken together, these findings implicate that SAL could protect endothelium against H2O2-induced injury via promoting mitochondrial biogenesis and function, thus preventing the overactivation of oxidative stress-related downstream signaling pathways.
    Oxidative medicine and cellular longevity 04/2014; 2014(12):904834. DOI:10.1155/2014/904834 · 3.36 Impact Factor
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