Possible role of endostatin in the antiangiogenic therapy of diabetic retinopathy

doi:10.1016/j.lfs.2015.06.017

Life Sciences

Volume 135, 15 August 2015, Pages 131-137

https://doi.org/10.1016/j.lfs.2015.06.017 Get rights and content

Abstract

Diabetic retinopathy is one of various complications of diabetes mellitus, which is one of the most prevalent chronic disorders in the modern world. Diabetic retinopathy is one of the secondary complications encountered by the patients suffering from chronic diabetes mellitus. Two major characterizing features of diabetic retinopathy are — macular edema and angiogenesis. It has been noted in the past few years that by controlling or completely inhibiting the factors contributing to the progression of events leading to angiogenesis, there is a noticeable amount of progress seen in the prevention and cure of the animal models of diabetic retinopathy. Endostatin is one such antiangiogenic agent being studied at present. It is a carbon terminal protein fragment obtained after cleavage from the carbon terminus of collagen XVIII. It is one of the most potent inhibitors of angiogenesis known at present and is currently undergoing clinical trials. Although the exact mechanism of action of endostatin is not completely known, various factors which are altered/influenced by the action of endostatin are being studied. These include the downregulation and activation/inactivation of various factors which have been proven to have some role in the progression of angiogenesis. Endostatin could be well exploited as a durable agent in the antiangiogenic therapy, once the clinical trials show positive results.

Graphical abstract

Introduction

Diabetes mellitus can unmistakably be addressed as one of the most abundantly found endocrine disorders in today's population. It is characterized by the altered levels of glucose in the blood, particularly on the elevated side — a condition, medically termed as, hyperglycemia. The causal factors of diabetes mellitus can be stated in the following two statements. The first form of diabetes mellitus (known of Type I diabetes mellitus) is caused due to the impairment in the normal secretions of the hormone — insulin, which is responsible for the transportation of blood glucose and its conversion into glucagon (a modified form of glucose which stores it in the various body cells, especially liver, adipose tissue and striated muscle cells). The second form of diabetes mellitus (known as Type II diabetes mellitus) is caused due to the peripheral resistance of the receptor cells of insulin — a condition termed as insulin resistance, in which the receptor cells stop responding to the stimulus of insulin [8], [9], [34].

The disorder of diabetes mellitus is not alone in causing various dysfunctions in the body; it also accompanies several other medical ailments commonly termed as diabetic complications, which contribute to the dysfunctions associated with it. These complications arise due to chronic untreated diabetes mellitus, the cause of which can be broadly stated as the adverse effects of the prevalent hyperglycemic conditions (in the body of a diabetic person) on the various other cells and/or tissues of the body such as neurons (diabetic neuropathy), blood vessels supplying eyes (diabetic retinopathy), blood vessels of kidneys (diabetic nephropathy) and various other small blood vessels of the body (diabetic microangiopathy) [15].

Section snippets

Diabetic retinopathy

Diabetic retinopathy is a complication of diabetes mellitus resulting in severe consequences. It is one of the leading causes of preventable blindness in the world. Vision loss in this disorder is attributed to the damage caused to the retinal cells due to the various dysfunctions which have occurred in the surrounding microvasculature. Its prevalence is reported to be very high all over the globe. Numerous data accounts have been presented after researches on various populations [3]. According

Angiogenesis as a significant event in diabetic retinopathy

Angiogenesis (or neovascularization) is the formation of new blood vessels from the existing vasculature as a result of various inflammatory responses occurring due to elevated blood glucose levels in the body of a diabetic patient. It occurs in response to the aftermath of the concessions of growth factors, vascular endothelial cells, extracellular matrix molecules, chemokines and cell signaling molecules. The process of angiogenesis is quite complex and takes place in response to the

Endostatin

Endostatin comprises of a segment of 20-kDa protein fragment obtained after proteolytic cleavage from the COOH terminal of collagen XVIII. This fragment has been studied for a long time and is now proven to have certain anti-proliferative and anti-angiogenic properties due to which it was found to be, effectively, showing indubitable anti-tumor properties. Till now, it has been proven useful in inhibiting as many as 65 divergent types of tumors. Moreover, it has been able to downregulate

Conclusion

Angiogenesis is one of the most scathing attributes encountered in the pathogenesis of proliferative diabetic retinopathy. The modern therapies are expressing their concern in finding a way to prevent (or treat, in case it has already occurred) angiogenesis so as to intercept the eventual blindness which occurs in the patients of diabetic retinopathy. Endostatin is one such serviceable molecule being researched upon for this preventive purpose. It is known to be a very potent inhibitor of

Conflict of interest statement

The authors declare that there are no conflicts of interest.

References (53)

A. Abdollahi et al.
Endostatin's antiangiogenic signaling network
Mol. Cell
(2004)
A.B. Aurora et al.
NF-κB balances vascular regression and angiogenesis via chromatin remodeling and NFAT displacement
Blood
(2010)
J. Folkman
Antiangiogenesis in cancer therapy—endostatin and its mechanisms of action
Exp. Cell Res.
(2006)
A.R. Hajrasouliha et al.
Exosomes from retinal astrocytes contain antiangiogenic components that inhibit laser-induced choroidal neovascularization
J. Biol. Chem.
(2013)
Q. Han et al.
Contributions of Zn(II)-binding to the structural stability of endostatin
FEBS Lett.
(2007)
M. Kappelmann et al.
AP-1/c-Jun transcription factors: regulation and function in malignant melanoma
Eur. J. Cell Biol.
(2014)
M.C. Moore et al.
Regulation of hepatic glucose uptake and storage in vivo
Adv. Nutr.
(2012)
J.S. Penn et al.
Vascular endothelial growth factor in eye disease
Prog. Retin. Eye Res.
(2008)
M.B. Ruzinova et al.
Effect of angiogenesis inhibition by Id loss and the contribution of bone-marrow-derived endothelial cells in spontaneous murine tumors
Cancer Cell
(2003)
H. Shi et al.
Nucleolin is a receptor that mediates antiangiogenic and antitumor activity of endostatin
Blood
(2007)

M.M. Vleugel et al.

c-Jun activation is associated with proliferation and angiogenesis in invasive breast cancer

Hum. Pathol.

(2006)

J. Zeng-Brouwers et al.

De novo expression of circulating biglycan evokes an innate inflammatory tissue response via MyD88/TRIF pathways

Matrix Biol.

(2014)

M. Zhang et al.

Downregulation of vascular endothelial growth factor and integrin β3 by endostatin in a mouse model of retinal neovascularization

Exp. Eye Res.

(2006)

T. Behl et al.

Diabetic nephropathy and diabetic retinopathy as major health burdens in modern era

World J. Pharm. Pharm. Sci.

(2014)

C.S. Boosani et al.

Proteolytically derived endogenous angioinhibitors originating from the extracellular matrix

Pharmaceuticals

(2011)

P. Carmeliet

Angiogenesis in health and disease

Nat. Med.

(2003)

S. Coronato et al.

Role of metalloproteinases and their inhibitors in tumors

Medicina (B Aires)

(2012)

J.K. Das et al.

PCB153-induced overexpression of ID3 contributes to the development of microvascular lesions

PLoS One

(2014)

R.A. DeFronzo et al.

Pathogenesis of NIDDM

R.A. DeFronzo et al.

Skeletal muscle insulin resistance is the primary defect in type 2 diabetes

Diabetes Care

(2009)

R.L. Eckert et al.

AP1 transcription factors in epidermal differentiation and skin cancer

J. Skin Cancer

(2013)

S. Evellin et al.

FOSL1 controls the assembly of endothelial cells into capillary tubes by direct repression of αv and β3 integrin transcription

Mol. Cell. Biol.

(2013)

J. Folkman

Angiogenesis

Annu. Rev. Med.

(2006)

J.A. Ford et al.

Current treatments in diabetic macular oedema: systematic review and meta-analysis

BMJ Open

(2013)

M.J. Fowler

Microvascular and macrovascular complications of diabetes

Clin. Diabetes

(2008)

Y. Fu et al.

Unraveling the mysteries of endostatin

Life

(2009)

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Review articlePossible role of endostatin in the antiangiogenic therapy of diabetic retinopathy

Abstract

Graphical abstract

Introduction

Section snippets

Diabetic retinopathy

Angiogenesis as a significant event in diabetic retinopathy

Endostatin

Conclusion

Conflict of interest statement

Mol. Cell

Blood

Exp. Cell Res.

J. Biol. Chem.

FEBS Lett.

Eur. J. Cell Biol.

Adv. Nutr.

Prog. Retin. Eye Res.

Cancer Cell

Blood

Hum. Pathol.

Matrix Biol.

Exp. Eye Res.

Diabetic nephropathy and diabetic retinopathy as major health burdens in modern era

World J. Pharm. Pharm. Sci.

Proteolytically derived endogenous angioinhibitors originating from the extracellular matrix

Pharmaceuticals

Angiogenesis in health and disease

Nat. Med.

Role of metalloproteinases and their inhibitors in tumors

Medicina (B Aires)

PCB153-induced overexpression of ID3 contributes to the development of microvascular lesions

PLoS One

Pathogenesis of NIDDM

Skeletal muscle insulin resistance is the primary defect in type 2 diabetes

Diabetes Care

AP1 transcription factors in epidermal differentiation and skin cancer

J. Skin Cancer

FOSL1 controls the assembly of endothelial cells into capillary tubes by direct repression of αv and β3 integrin transcription

Mol. Cell. Biol.

Angiogenesis

Annu. Rev. Med.

Current treatments in diabetic macular oedema: systematic review and meta-analysis

BMJ Open

Microvascular and macrovascular complications of diabetes

Clin. Diabetes

Unraveling the mysteries of endostatin

Life

Review article
Possible role of endostatin in the antiangiogenic therapy of diabetic retinopathy