The unconventional role of acid sphingomyelinase in regulation of retinal microangiopathy in diabetic human and animal models

Madalina Opreanu, Maria Tikhonenko, Svetlana Bozack, Todd A. Lydic, Gavin E. Reid, Kelly M. McSorley, Andrew Sochacki, Gloria I. Perez, Walter J. Esselman, Timothy Kern, Richard Kolesnick, Maria B. Grant, Julia V. Busik

Research output: Contribution to journalArticle

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Abstract

OBJECTIVE - Acid sphingomyelinase (ASM) is an important early responder in inflammatory cytokine signaling. The role of ASM in retinal vascular inflammation and vessel loss associated with diabetic retinopathy is not known and represents the goal of this study. RESEARCH DESIGN AND METHODS - Protein and gene expression profiles were determined by quantitative RT-PCR and Western blot. ASM activity was determined using Amplex Red sphingomyelinase assay. Caveolar lipid composition was analyzed by nano-electrospray ionization tandem mass spectrometry. Streptozotocin-induced diabetes and retinal ischemia-reperfusion models were used in in vivo studies. RESULTS - We identify endothelial caveolae-associated ASM as an essential component in mediating inflammation and vascular pathology in in vivo and in vitro models of diabetic retinopathy. Human retinal endothelial cells (HREC), in contrast with glial and epithelial cells, express the plasma membrane form of ASM that overlaps with caveolin-1. Treatment of HREC with docosahexaenoic acid (DHA) specifically reduces expression of the caveolaeassociated ASM, prevents a tumor necrosis factor-a-induced increase in the ceramide-to-sphingomyelin ratio in the caveolae, and inhibits cytokine-induced inflammatory signaling. ASM is expressed in both vascular and neuroretina; however, only vascular ASM is specifically increased in the retinas of animal models at the vasodegenerative phase of diabetic retinopathy. The absence of ASM in ASM-/- mice or inhibition of ASM activity by DHA prevents acellular capillary formation. CONCLUSIONS - This is the first study demonstrating activation of ASM in the retinal vasculature of diabetic retinopathy animal models. Inhibition of ASM could be further explored as a potential therapeutic strategy in treating diabetic retinopathy.

Original languageEnglish (US)
Pages (from-to)2370-2378
Number of pages9
JournalDiabetes
Volume60
Issue number9
DOIs
StatePublished - Sep 2011
Externally publishedYes

Fingerprint

Sphingomyelin Phosphodiesterase
Diabetic Angiopathies
Animal Models
Acids
Diabetic Retinopathy
Blood Vessels
Caveolae
Retinal Vessels
Docosahexaenoic Acids
Endothelial Cells
Cytokines
Inflammation
Caveolin 1
Experimental Diabetes Mellitus
Sphingomyelins
Electrospray Ionization Mass Spectrometry
Ceramides
Tandem Mass Spectrometry
Transcriptome
Neuroglia

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Opreanu, M., Tikhonenko, M., Bozack, S., Lydic, T. A., Reid, G. E., McSorley, K. M., ... Busik, J. V. (2011). The unconventional role of acid sphingomyelinase in regulation of retinal microangiopathy in diabetic human and animal models. Diabetes, 60(9), 2370-2378. https://doi.org/10.2337/db10-0550

The unconventional role of acid sphingomyelinase in regulation of retinal microangiopathy in diabetic human and animal models. / Opreanu, Madalina; Tikhonenko, Maria; Bozack, Svetlana; Lydic, Todd A.; Reid, Gavin E.; McSorley, Kelly M.; Sochacki, Andrew; Perez, Gloria I.; Esselman, Walter J.; Kern, Timothy; Kolesnick, Richard; Grant, Maria B.; Busik, Julia V.

In: Diabetes, Vol. 60, No. 9, 09.2011, p. 2370-2378.

Research output: Contribution to journalArticle

Opreanu, M, Tikhonenko, M, Bozack, S, Lydic, TA, Reid, GE, McSorley, KM, Sochacki, A, Perez, GI, Esselman, WJ, Kern, T, Kolesnick, R, Grant, MB & Busik, JV 2011, 'The unconventional role of acid sphingomyelinase in regulation of retinal microangiopathy in diabetic human and animal models', Diabetes, vol. 60, no. 9, pp. 2370-2378. https://doi.org/10.2337/db10-0550
Opreanu, Madalina ; Tikhonenko, Maria ; Bozack, Svetlana ; Lydic, Todd A. ; Reid, Gavin E. ; McSorley, Kelly M. ; Sochacki, Andrew ; Perez, Gloria I. ; Esselman, Walter J. ; Kern, Timothy ; Kolesnick, Richard ; Grant, Maria B. ; Busik, Julia V. / The unconventional role of acid sphingomyelinase in regulation of retinal microangiopathy in diabetic human and animal models. In: Diabetes. 2011 ; Vol. 60, No. 9. pp. 2370-2378.
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abstract = "OBJECTIVE - Acid sphingomyelinase (ASM) is an important early responder in inflammatory cytokine signaling. The role of ASM in retinal vascular inflammation and vessel loss associated with diabetic retinopathy is not known and represents the goal of this study. RESEARCH DESIGN AND METHODS - Protein and gene expression profiles were determined by quantitative RT-PCR and Western blot. ASM activity was determined using Amplex Red sphingomyelinase assay. Caveolar lipid composition was analyzed by nano-electrospray ionization tandem mass spectrometry. Streptozotocin-induced diabetes and retinal ischemia-reperfusion models were used in in vivo studies. RESULTS - We identify endothelial caveolae-associated ASM as an essential component in mediating inflammation and vascular pathology in in vivo and in vitro models of diabetic retinopathy. Human retinal endothelial cells (HREC), in contrast with glial and epithelial cells, express the plasma membrane form of ASM that overlaps with caveolin-1. Treatment of HREC with docosahexaenoic acid (DHA) specifically reduces expression of the caveolaeassociated ASM, prevents a tumor necrosis factor-a-induced increase in the ceramide-to-sphingomyelin ratio in the caveolae, and inhibits cytokine-induced inflammatory signaling. ASM is expressed in both vascular and neuroretina; however, only vascular ASM is specifically increased in the retinas of animal models at the vasodegenerative phase of diabetic retinopathy. The absence of ASM in ASM-/- mice or inhibition of ASM activity by DHA prevents acellular capillary formation. CONCLUSIONS - This is the first study demonstrating activation of ASM in the retinal vasculature of diabetic retinopathy animal models. Inhibition of ASM could be further explored as a potential therapeutic strategy in treating diabetic retinopathy.",
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AU - Opreanu, Madalina

AU - Tikhonenko, Maria

AU - Bozack, Svetlana

AU - Lydic, Todd A.

AU - Reid, Gavin E.

AU - McSorley, Kelly M.

AU - Sochacki, Andrew

AU - Perez, Gloria I.

AU - Esselman, Walter J.

AU - Kern, Timothy

AU - Kolesnick, Richard

AU - Grant, Maria B.

AU - Busik, Julia V.

PY - 2011/9

Y1 - 2011/9

N2 - OBJECTIVE - Acid sphingomyelinase (ASM) is an important early responder in inflammatory cytokine signaling. The role of ASM in retinal vascular inflammation and vessel loss associated with diabetic retinopathy is not known and represents the goal of this study. RESEARCH DESIGN AND METHODS - Protein and gene expression profiles were determined by quantitative RT-PCR and Western blot. ASM activity was determined using Amplex Red sphingomyelinase assay. Caveolar lipid composition was analyzed by nano-electrospray ionization tandem mass spectrometry. Streptozotocin-induced diabetes and retinal ischemia-reperfusion models were used in in vivo studies. RESULTS - We identify endothelial caveolae-associated ASM as an essential component in mediating inflammation and vascular pathology in in vivo and in vitro models of diabetic retinopathy. Human retinal endothelial cells (HREC), in contrast with glial and epithelial cells, express the plasma membrane form of ASM that overlaps with caveolin-1. Treatment of HREC with docosahexaenoic acid (DHA) specifically reduces expression of the caveolaeassociated ASM, prevents a tumor necrosis factor-a-induced increase in the ceramide-to-sphingomyelin ratio in the caveolae, and inhibits cytokine-induced inflammatory signaling. ASM is expressed in both vascular and neuroretina; however, only vascular ASM is specifically increased in the retinas of animal models at the vasodegenerative phase of diabetic retinopathy. The absence of ASM in ASM-/- mice or inhibition of ASM activity by DHA prevents acellular capillary formation. CONCLUSIONS - This is the first study demonstrating activation of ASM in the retinal vasculature of diabetic retinopathy animal models. Inhibition of ASM could be further explored as a potential therapeutic strategy in treating diabetic retinopathy.

AB - OBJECTIVE - Acid sphingomyelinase (ASM) is an important early responder in inflammatory cytokine signaling. The role of ASM in retinal vascular inflammation and vessel loss associated with diabetic retinopathy is not known and represents the goal of this study. RESEARCH DESIGN AND METHODS - Protein and gene expression profiles were determined by quantitative RT-PCR and Western blot. ASM activity was determined using Amplex Red sphingomyelinase assay. Caveolar lipid composition was analyzed by nano-electrospray ionization tandem mass spectrometry. Streptozotocin-induced diabetes and retinal ischemia-reperfusion models were used in in vivo studies. RESULTS - We identify endothelial caveolae-associated ASM as an essential component in mediating inflammation and vascular pathology in in vivo and in vitro models of diabetic retinopathy. Human retinal endothelial cells (HREC), in contrast with glial and epithelial cells, express the plasma membrane form of ASM that overlaps with caveolin-1. Treatment of HREC with docosahexaenoic acid (DHA) specifically reduces expression of the caveolaeassociated ASM, prevents a tumor necrosis factor-a-induced increase in the ceramide-to-sphingomyelin ratio in the caveolae, and inhibits cytokine-induced inflammatory signaling. ASM is expressed in both vascular and neuroretina; however, only vascular ASM is specifically increased in the retinas of animal models at the vasodegenerative phase of diabetic retinopathy. The absence of ASM in ASM-/- mice or inhibition of ASM activity by DHA prevents acellular capillary formation. CONCLUSIONS - This is the first study demonstrating activation of ASM in the retinal vasculature of diabetic retinopathy animal models. Inhibition of ASM could be further explored as a potential therapeutic strategy in treating diabetic retinopathy.

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