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

Ding, Hong; Howarth, Andrew G; Pannirselvam, Malarvannan; Anderson, Todd J.; Severson, David L.; Wiehler, William B.; Triggle, Chris R.; Tuana, Balwant S.

doi:10.1152/ajpheart.00037.2005

Cited by 25 publications

(27 citation statements)

References 42 publications

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“…Smoke exposure also elicits altered expression of several ion transporters that play essential roles in the cardiac action potential maintaining contractile rhythmicity, and notably, genes involved in vascular tone and endothelial dysfunction, a recognized precursor in the development of atherosclerosis. 40, 41 Among genes most sensitive to smoke exposure are several circadian genes, ( Nr1d1 , Dbp , Bhlhe40) , consistent with previously reported disruption of circadian processes by smoking that has been linked to health disorders and myocardial infarction. 42–45 …”

Section: Resultssupporting

confidence: 86%

Impaired Transcriptional Response of the Murine Heart to Cigarette Smoke in the Setting of High Fat Diet and Obesity

Tilton

Karin

Webb-Robertson

et al. 2013

Chem. Res. Toxicol.

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Smoking and obesity are each well-established risk factors for cardiovascular heart disease, which together impose earlier onset and greater severity of disease. To identify early signaling events in the response of the heart to cigarette smoke exposure within the setting of obesity, we exposed normal weight and high fat diet-induced obese (DIO) C57BL/6 mice to repeated inhaled doses of mainstream (MS) or sidestream (SS) cigarette smoke administered over a two week period, monitoring effects on both cardiac and pulmonary transcriptomes. MS smoke (250 µg wet total particulate matter (WTPM)/L, 5h/day) exposures elicited robust cellular and molecular inflammatory responses in the lung with 1466 differentially expressed pulmonary genes (p<0.01) in normal weight animals, and a muchattenuated response (463 genes) in the hearts of the same animals. In contrast, exposures to SS smoke (85 µg WTPM/L) with an equivalent CO concentration as that of MS smoke (~250 CO ppm), induced a weak pulmonary response (328 genes), but an extensive cardiac response (1590 genes). SS smoke, and to a lesser extent MS smoke preferentially elicited hypoxia- and stress-responsive genes as well as genes predicting early changes of vascular smooth muscle and endothelium, precursors of cardiovascular disease. The most sensitive smoke-induced cardiac transcriptional changes of normal weight mice were largely absent in DIO mice after smoke exposure, while genes involved in fatty acid utilization were unaffected. At the same time, smoke exposure suppressed multiple proteome maintenance genes induced in the hearts of DIO mice. Together these results underscore the sensitivity of the heart to SS smoke and reveal adaptive responses in healthy individuals that are absent in the setting of high fat diet and obesity.

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Section: Resultssupporting

confidence: 86%

Impaired Transcriptional Response of the Murine Heart to Cigarette Smoke in the Setting of High Fat Diet and Obesity

Tilton

Karin

Webb-Robertson

et al. 2013

Chem. Res. Toxicol.

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“…APPL1 expression and adiponectin-evoked vasodilation are decreased in small mesenteric arteries of db/db diabetic mice. To explore the pathophysiological relevance of the above in vitro findings, we next compared APPL1 mRNA expression in several tissues in C57BL/KsJ db/ϩ lean mice and db/db diabetic mice, an established animal model with endothelial dysfunction (27,37). db/db diabetic mice showed significantly increased body weight (52.4 Ϯ 3.3 vs. 29.1 Ϯ 1.6 g, P Ͻ 0.01) and higher plasma levels of blood glucose (483.6 Ϯ 24.7 vs. 197.2 Ϯ 11.5 mg/dl, P Ͻ 0.01), triglycerides (238.9 Ϯ 15.2 vs. 92.5 Ϯ 6.8 mg/dl, P Ͻ 0.01), insulin (14.3 Ϯ 1.3 vs. 1.2 Ϯ 0.1 ng/ml, P Ͻ 0.01), and cholesterol (164.8 Ϯ 9.2 vs. 81.7 Ϯ 7.3 mg/dl, P Ͻ 0.01) compared with their lean littermates.…”

Section: Resultsmentioning

confidence: 99%

Adiponectin-Induced Endothelial Nitric Oxide Synthase Activation and Nitric Oxide Production Are Mediated by APPL1 in Endothelial Cells

et al. 2007

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, and the complex formation between eNOS and heat shock protein 90, resulting in a marked reduction of NO production. Adenovirus-mediated overexpression of a constitutively active version of AMPK reversed these changes. In db/db diabetic mice, both APPL1 expression and adiponectin-induced vasodilation were significantly decreased compared with their lean littermates. Taken together, these results suggest that APPL1 acts as a common downstream effector of AdipoR1 and -R2, mediating adiponectin-evoked endothelial NO production and endothelium-dependent vasodilation. Diabetes 56: [1387][1388][1389][1390][1391][1392][1393][1394] 2007 E ndothelial dysfunction, characterized by decreased production and/or bioactivity of nitric oxide (NO) and impaired endothelium-dependent vasodilation, is a key mediator that links obesity, diabetes, and cardiovascular diseases (1). Dysfunction of the endothelium in conduit arteries is a well-established antecedent of hypertension and atherosclerosis, whereas dysfunction of peripheral vascular endothelium at the arteriolar and capillary level contributes to the pathogenesis of insulin resistance and the metabolic syndrome (2). On the other hand, insulin resistance aggravates endothelial dysfunction. Therapeutic interventions in animal models and humans have demonstrated that improving endothelial function ameliorates insulin resistance, while increasing insulin sensitivity alleviates endothelial dysfunction (3).Adiponectin, an insulin-sensitizing adipokine secreted predominantly from adipocytes, possesses potent protective effects against endothelial dysfunction (4). Unlike most adipokines, plasma levels of adiponectin are decreased in obese individuals and patients with insulin resistance, type 2 diabetes, and cardiovascular diseases. An independent association between serum levels of adiponectin and endothelium-dependent vasodilation has been repeatedly documented (5-7). Hypoadiponectinemia has been closely linked to impairment in endotheliumdependent vasodilation in both normal subjects and patients with hypertension and type 2 diabetes. Consistent with these clinical findings, adiponectin-deficient mice exhibit reduced endothelium-dependent vasodilation on an atherogenic diet (6), increased neointimal hyperplasia after acute vascular injury (8,9), and elevated blood pressure compared with their wild-type littermates (10). On the other hand, both adenovirus-mediated overexpression of full-length adiponectin and transgenic overexpression of globular adiponectin result in a marked alleviation of atherosclerotic lesion in apolipoprotein E-deficient mice (11) and also cause a significant amelioration of endothelial dysfunction and hypertension (10) in obese mice.The endothelium-protective functions of adiponectin are mediated, at least in part, by its ability to increase the production of NO, a vasodilator synthesized by endothelial NO synthase (eNOS) from the precursor L-arginine (4,7,12). NO protects the vascular system by enhancing vasodilation and inhibiting platelet aggregation,...

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“…In fact, a prominent feature of these patients is often the presence of endothelial dysfunction, including impaired NO response (78,79). It is conceivable that the administration of an HBOC into the circulation will exacerbate their impaired NO…”

Section: Introductionmentioning

confidence: 99%

Enhancing Nitrite Reductase Activity of Modified Hemoglobin: Bis-tetramers and Their PEGylated Derivatives

Lui

Kluger

2009

Biochemistry

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The clinical evaluation of stabilized tetrameric hemoglobin as alternatives to red cells revealed that the materials caused significant increases in blood pressure and related problems and this was attributed to the scavenging of nitric oxide and extravasation. The search for materials with reduced vasoactivity led to the report that conjugates of hemoglobin tetramers and polyethylene glycol (PEG) chains did not elicit these pressor effects. However, this material does not deliver oxygen efficiently due to its lack of cooperativity and high oxygen affinity, making it unsuitable as an oxygen carrier. It has been recently reported that PEGconjugated hemoglobin converts nitrite to nitric oxide at a faster rate than does the native protein, which may compensate for the scavenging of nitric oxide. It is therefore important to alter hemoglobin in order to enhance nitrite reductase activity while retaining its ability to deliver oxygen. If the beneficial effect of PEG is associated with the increased size reducing extravasation, this can also be achieved by coupling cross-linked tetramers to one another, giving materials with appropriate oxygen affinity and cooperativity for use as circulating oxygen carriers. In the present study it is shown that cross-linked bis-tetramers with good oxygen delivery potential have enhanced nitrite reductase activity with k obs = 0.70 M -1 s -1 (24 °C), compared to native protein and cross-linked tetramers, k obs = 0.25 M -1 s -1 and k obs = 0.52 M -1 s -1 , respectively, but are less active in reduction of nitrite than Hb-PEG5K 2 (k obs = 2.5 M -1 s -1 ). However, conjugation of four PEG chains to the bis-tetramer (at each β-Cys-93) produces a material with greatly increased nitrite reductase activity (k obs = 1.8 M -1 s -1 ) while retaining cooperativity (P 50 = 4.1, n 50 = 2.4). Thus, PEGylated bistetramers combine increased size and enhanced nitrite reductase activity expected for decreased vasoactivity with characteristics of an acceptable HBOC.

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

Cited by 25 publications

References 42 publications

Impaired Transcriptional Response of the Murine Heart to Cigarette Smoke in the Setting of High Fat Diet and Obesity

Impaired Transcriptional Response of the Murine Heart to Cigarette Smoke in the Setting of High Fat Diet and Obesity

Adiponectin-Induced Endothelial Nitric Oxide Synthase Activation and Nitric Oxide Production Are Mediated by APPL1 in Endothelial Cells

Enhancing Nitrite Reductase Activity of Modified Hemoglobin: Bis-tetramers and Their PEGylated Derivatives

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