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Imaging the effect of receptor for advanced glycation endproducts on angiogenic response to hindlimb ischemia in diabetes

Tekabe, Yared; Shen, Xiaoping; Luma, Joane; Weisenberger, Drew; Yan, Shi Fang; Haubner, Roland; Schmidt, Ann Marie; Johnson, Lynne
BACKGROUND: Receptor for advanced glycation endproducts (RAGE) expression contributes to the impaired angiogenic response to limb ischemia in diabetes. The aim of this study was to detect the effect of increased expression of RAGE on the angiogenic response to limb ischemia in diabetes by targeting alphavbeta3 integrin with 99mTc-labeled Arg-Gly-Asp (RGD). METHODS: Male wild-type (WT) C57BL/6 mice were either made diabetic or left as control for 2 months when they underwent femoral artery ligation. Four groups were studied at days 3 to 7 after ligation: WT without diabetes (NDM) (n = 14), WT with diabetes (DM) (n = 14), RAGE-/- NDM (n = 16), and RAGE-/- DM (n = 14). Mice were injected with 99mTc-HYNIC-RGD and imaged. Count ratios for ischemic/non-ischemic limbs were measured. Muscle was stained for RAGE, alphavbeta3, and lectins. RESULTS: There was no difference in count ratio between RAGE-/- and WT NDM groups. Mean count ratio was lower for WT DM (1.38 +/- 0.26) vs. WT NDM (1.91 +/- 0.34) (P<0.001). Mean count ratio was lower for the RAGE-/- DM group than for RAGE-/- NDM group (1.75 +/- 0.22 vs. 2.02 +/- 0.29) (P<0.001) and higher than for the WT DM group (P<0.001). Immunohistopathology supported the scan findings. CONCLUSIONS: In vivo imaging of alphavbeta3 integrin can detect the effect of RAGE on the angiogenic response to limb ischemia in diabetes.
PMCID:3192466
PMID: 22214528
ISSN: 2191-219x
CID: 778832

Alternative splicing of RAGE: roles in biology and disease

Kalea, Anastasia Z; Schmidt, Ann Marie; Hudson, Barry I
The Receptor for Advanced Glycation End-products (RAGE) is a complex, multi-ligand signaling system implicated in the pathogenesis of diabetes, cardiovascular disease and various cancers. RAGE undergoes extensive alternative splicing to produce a variety of transcripts with diverse functions, including soluble antagonists and variants with altered ligand binding domains. Studies focused on the major soluble variant (RAGEv1/esRAGE) have revealed this to function by binding RAGE-ligands and preventing activation of RAGE signaling in vascular and tumor cells. Furthermore, measurement of this variant in human serum has revealed that RAGEv1/esRAGE levels may represent a novel biomarker for RAGE-ligand related pathogenic states. Understanding the full plethora of RAGE alternative splicing and its regulation is central to elucidating the role of RAGE in biology and disease
PMID: 21622207
ISSN: 1093-4715
CID: 141665

Human vascular endothelial cells: a model system for studying vascular inflammation in diabetes and atherosclerosis

Onat, Duygu; Brillon, David; Colombo, Paolo C; Schmidt, Ann Marie
The vascular endothelium is the inner lining of blood vessels serving as autocrine and paracrine organ that regulates vascular wall function. Endothelial dysfunction is recognized as initial step in the atherosclerotic process and is well advanced in diabetes, even before the manifestation of end-organ damage. Strategies capable of assessing changes in vascular endothelium at the preclinical stage hold potential to refine cardiovascular risk. In vitro cell culture is useful in understanding the interaction of endothelial cells with various mediators; however, it is often criticized due to the uncertain relevance of results to humans. Although circulating endothelial cells, endothelial microparticles, and progenitor cells opened the way for ex vivo studies, a recently described method for obtaining primary endothelial cells through endovascular biopsy allows direct characterization of endothelial phenotype in humans. In this article, we appraise the use of endothelial cell-based methodologies to study vascular inflammation in diabetes and atherosclerosis
PMCID:3311155
PMID: 21337131
ISSN: 1539-0829
CID: 134273

Differential impact of diabetes and hypertension in the brain: adverse effects in white matter

Yang, Christina; DeVisser, Adriena; Martinez, Jose A; Poliakov, Ilia; Rosales-Hernandez, Alma; Ayer, Amit; Garven, Alexandra; Zaver, Shaila; Rincon, Natalia; Xu, Kevin; Tuor, Ursula I; Schmidt, Ann Marie; Toth, Cory
Humans subjected to diabetes mellitus (DM) and/or hypertension (HTN) develop cognitive decline, cerebral atrophy and white matter abnormalities, but the relative effects of DM and HTN upon myelin and axonal integrity is unknown. We studied models of Type 1 (streptozotocin-induced) and Type 2 DM (ZDF) +/- HTN (ZSF-1, SHR) in adult rats using magnetic resonance imaging (MRI) and structural and molecular techniques. Type 1 or 2 DM independently led to loss of myelin associated with changes with MRI T2 and magnetization tensor ratios throughout white matter regions. HTN's effect on myelin loss was minimal. Loss of oligodendroglia and myelin proteins was only identified in either Type 1 or Type 2 DM. Activation of the signal transduction pathways initiated by the receptor for advanced glycation end products (AGEs), RAGE, including upregulation of the signal transducer nuclear factor (NF) kappaB only occurred with DM. Diabetes is a greater contributor to white matter loss than hypertension in the rat brain, while hypertension only plays a mild additive effect upon neurodegeneration in the presence of diabetes.
PMID: 21324363
ISSN: 0969-9961
CID: 778842

Advanced Glycation End Product Recognition by the Receptor for AGEs

Xue, Jing; Rai, Vivek; Singer, David; Chabierski, Stefan; Xie, Jingjing; Reverdatto, Sergey; Burz, David S; Schmidt, Ann Marie; Hoffmann, Ralf; Shekhtman, Alexander
Nonenzymatic protein glycation results in the formation of advanced glycation end products (AGEs) that are implicated in the pathology of diabetes, chronic inflammation, Alzheimer's disease, and cancer. AGEs mediate their effects primarily through a receptor-dependent pathway in which AGEs bind to a specific cell surface associated receptor, the Receptor for AGEs (RAGE). N(varepsilon)-carboxy-methyl-lysine (CML) and N(varepsilon)-carboxy-ethyl-lysine (CEL), constitute two of the major AGE structures found in tissue and blood plasma, and are physiological ligands of RAGE. The solution structure of a CEL-containing peptide-RAGE V domain complex reveals that the carboxyethyl moiety fits inside a positively charged cavity of the V domain. Peptide backbone atoms make specific contacts with the V domain. The geometry of the bound CEL peptide is compatible with many CML (CEL)-modified sites found in plasma proteins. The structure explains how such patterned ligands as CML (CEL)-proteins bind to RAGE and contribute to RAGE signaling
PMCID:3150472
PMID: 21565706
ISSN: 1878-4186
CID: 134164

Rage Gene Deletion inhibits the Development and Progression of Ductal Neoplasia and Prolongs Survival in a Mouse Model of Pancreatic Cancer [Meeting Abstract]

DiNorcia, Joseph; Lee, Minna K.; Moroziewicz, Dorota N.; Winner, Megan D.; Suman, Paritosh; Bao, Fei; Remotti, Helen; Zou, Yu Shan; Yan, Shi Fang; Qiu, Wanglong; Su, Gloria H.; Schmidt, Ann Marie; Allendorf, John D.
ISI:000290167304635
ISSN: 0016-5085
CID: 3502102

Association of serum soluble receptor for advanced glycation end-products with subclinical cerebrovascular disease: the Northern Manhattan Study (NOMAS)

Hudson, Barry I; Moon, Yeseon Park; Kalea, Anastasia Z; Khatri, Minesh; Marquez, Chensy; Schmidt, Ann Marie; Paik, Myunghee C; Yoshita, Mitsuhiro; Sacco, Ralph L; DeCarli, Charles; Wright, Clinton B; Elkind, Mitchell S V
OBJECTIVE: Serum levels of the soluble receptor for advanced glycation end-products (sRAGE) have been associated with risk of cardiovascular disease. We hypothesized that sRAGE levels are associated with subclinical cerebrovascular disease in an ethnically diverse population. METHODS: Clinically stroke-free participants in the multi-ethnic Northern Manhattan Study (NOMAS) underwent brain MRI to quantify subclinical brain infarcts (SBI) and white matter hyperintensity volume (WMHV) (n = 1102). Serum levels of sRAGE were measured by ELISA. Logistic and multiple linear regression were employed to estimate associations of sRAGE with SBI and WMHV, after adjusting for demographics and vascular risk factors. RESULTS: Median sRAGE levels were significantly lower in Hispanics (891.9 pg/ml; n = 708) and non-Hispanic blacks (757.4 pg/ml; n = 197) than in non-Hispanic whites (1120.5 pg/ml; n = 170), and these differences remained after adjusting for other risk factors. Interactions were observed by race-ethnicity between sRAGE levels and MRI measurements, including for SBI in Hispanics (p = 0.04) and WMHV among blacks (p = 0.03). In Hispanics, increasing sRAGE levels were associated with a lower odds of SBI, with those in the upper sRAGE quartile displaying a 50% lower odds of SBI after adjusting for sociodemographic and vascular risk factors (p = 0.05). Among blacks, those in the upper quartile of sRAGE had a similarly reduced increased risk of SBI (p = 0.06) and greater WMHV (p = 0.04). CONCLUSION: Compared to whites, Hispanics and blacks have significantly lower sRAGE levels, and these levels were associated with more subclinical brain disease. Taken together, these findings suggest sRAGE levels may be significantly influence by ethnicity. Further studies of sRAGE and stroke risk, particularly in minorities, are warranted.
PMCID:3089661
PMID: 21316677
ISSN: 0021-9150
CID: 778852

S100/calgranulins EN-RAGEing the blood vessels: implications for inflammatory responses and atherosclerosis

Hofmann Bowman, Marion A; Schmidt, Ann Marie
Atherosclerosis remains the leading cause of death in the western countries and represents a complex chronic inflammatory process whose regulation is dependent on a network of cytokine and chemokine signaling between key cells such as endothelial cells, monocytes, dendritic cells, lymphocytes and smooth muscle cells. This review focuses on the biology and function of S100 proteins and their receptor RAGE with respect to the multifactorial process leading to atherosclerosis, plaque rupture, and aortic wall remodeling.
PMCID:3244046
PMID: 22200033
ISSN: 2160-200x
CID: 778862

RAGE signaling significantly impacts tumorigenesis and hepatic tumor growth in murine models of colorectal carcinoma

DiNorcia, Joseph; Moroziewicz, Dorota N; Ippagunta, Nikalesh; Lee, Minna K; Foster, Mark; Rotterdam, Heidrun Z; Bao, Fei; Zhou, Yu Shan; Yan, Shi Fang; Emond, Jean; Schmidt, Ann Marie; Allendorf, John D
BACKGROUND: The receptor for advanced glycation end-products (RAGE) is a cell surface receptor implicated in tumor cell proliferation and migration. We hypothesized that RAGE signaling impacts tumorigenesis and metastatic tumor growth in murine models of colorectal carcinoma. MATERIALS AND METHODS: Tumorigenesis: Apc (1638N/+) mice were crossed with Rage (-/-) mice in the C57BL/6 background to generate Apc (1638N/+)/Rage (-/-) mice. Metastasis: BALB/c mice underwent portal vein injection with CT26 cells (syngeneic) and received daily soluble (s)RAGE or vehicle. Rage (-/-) mice and Rage (+/+) controls underwent portal vein injection with MC38 cells (syngeneic). Rage (+/+) mice underwent portal vein injection with MC38 cells after stable transfection with full-length RAGE or mock transfection control. RESULTS: Tumorigenesis: Apc (1638N/+)/Rage (-/-) mice had reduced tumor incidence, size, and histopathologic grade. Metastasis: Pharmacological blockade of RAGE with sRAGE or genetic deletion of Rage reduced hepatic tumor incidence, nodules, and burden. Gain of function by transfection with full-length RAGE increased hepatic tumor burden compared to vector control MC38 cells. CONCLUSION: RAGE signaling plays an important role in tumorigenesis and hepatic tumor growth in murine models of colorectal carcinoma. Further work is needed to target the ligand-RAGE axis for possible prophylaxis and treatment of primary and metastatic colorectal carcinoma
PMCID:4334905
PMID: 20824364
ISSN: 1873-4626
CID: 140587

Advanced glycation end products on stored red blood cells increase endothelial reactive oxygen species generation through interaction with receptor for advanced glycation end products

Mangalmurti, Nilam S; Chatterjee, Shampa; Cheng, Guanjun; Andersen, Emily; Mohammed, Aishat; Siegel, Donald L; Schmidt, Ann Marie; Albelda, Steven M; Lee, Janet S
BACKGROUND: Recent evidence suggests that storage-induced alterations of the red blood cell (RBC) are associated with adverse consequences in susceptible hosts. As RBCs have been shown to form advanced glycation end products (AGEs) after increased oxidative stress and under pathologic conditions, we examined whether stored RBCs undergo modification with the specific AGE N-(carboxymethyl)lysine (N(epsilon) -CML) during standard blood banking conditions. STUDY DESIGN AND METHODS: Purified, fresh RBCs from volunteers were compared to stored RBCs (35-42 days old) obtained from the blood bank. N(epsilon) -CML formation was quantified using a competitive enzyme-linked immunosorbent assay. The receptor for advanced glycation end products (RAGE) was detected in human pulmonary microvascular endothelial cells (HMVEC-L) by real-time polymerase chain reaction, Western blotting, and flow cytometry. Intracellular reactive oxygen species (ROS) generation was measured by the use of 5-(and 6-)chloromethyl-2',7'-dichlorodihydrofluorescein diacetate, acetyl ester-based assays. RESULTS: Stored RBCs showed increased surface N(epsilon) -CML formation when compared with fresh RBCs. HMVEC-L showed detectable surface RAGE expression constitutively. When compared to fresh RBCs, stored RBCs triggered increased intracellular ROS generation in both human umbilical vein endothelial cells and HMVEC-L. RBC-induced endothelial ROS generation was attenuated in the presence of soluble RAGE or RAGE blocking antibody. CONCLUSIONS: The formation of the AGE N(epsilon) -CML on the surface of stored RBCs is one functional consequence of the storage lesion. AGE-RAGE interactions may be one mechanism by which transfused RBCs cause endothelial cell damage.
PMCID:3010325
PMID: 20492604
ISSN: 0041-1132
CID: 778872