Study suggests new way of preventing diabetes-associated blindness Reporting on their study with lab-grown human cells, researchers at The Johns Hopkins University and the University of Maryland say that blocking a second blood vessel growth protein, along with one that is already well-known, could offer a new way to treat and prevent a blinding eye disease caused by diabetes. A summary of the study appears online May 25 in Proceedings of the National Academy of Sciences. The disease, diabetic retinopathy , is the most common cause of vision loss in working-age adults in the United States. Diabetic eye disease occurs when the normal blood vessels in the eye are replaced over time with abnormal, leaky, fragile blood vessels that leak fluid or bleed into the eye, damaging the light-sensitive retina and causing blindness. Forty to 45 percent of Americans with diabetes have diabetic retinopathy, according to the National Eye Institute. Laser-sealing eye blood vessels can save central vision, but this often sacrifices peripheral and night vision, according to Akrit Sodhi, M.D., Ph.D. , an assistant professor of ophthalmology at the Johns Hopkins University School of Medicine. Several recently developed drugs—bevacizumab, ranibizumab and aflibercept—can help treat these blood vessels by blocking the action of VEGF, a so-called growth factor released as part of a chain of signals in response to low oxygen levels, which stimulates the growth of new, often abnormal, blood vessels. But studies have shown that although these drugs slow progression to proliferative diabetic retinopathy, it does not reliably prevent it. Looking for an explanation, postdoctoral fellow Savalan Babapoor-Farrokhran, M.D., and Kathleen Jee, a student at the school of medicine who will begin her residency in ophthalmology at the Wilmer Eye Institute at Johns Hopkins next year, tested levels of VEGF in samples of fluid from the eye taken from healthy people, people with diabetes who did not have diabetic retinopathy and people with diabetic retinopathy of varying severity. While levels of VEGF tended to be higher in those with proliferative diabetic retinopathy, some of their fluid had less VEGF than did the healthy participants. But even the low-VEGF fluid from patients with proliferative diabetic retinopathy stimulated blood vessel growth in lab-grown cells. "The results suggested to us that although VEFG clearly plays an important role in blood vessel growth, it's not the only factor," Sodhi says. A series of experiments in lab-grown human cells and mice revealed a second culprit, a protein called angiopoietin-like 4. When the researchers blocked the action of both VEGF and angiopoietin-like 4 in fluid from the eyes of people with proliferative diabetic retinopathy, it markedly reduced blood vessel growth in lab-grown cells. If a drug can be found that safely blocks the second protein's action in patients' eyes, it might be combined with the anti-VEGF drugs to prevent many cases of proliferative diabetic retinopathy, Sodhi suggests. The team is now investigating whether angiopoietin-like 4 might also play a role in other eye diseases, such as macular degeneration, which destroys the central portion of the retina. Explore further: Lucentis approved for diabetic retinopathy More information: Angiopoietin-like 4 is a potent angiogenic factor and a novel therapeutic target for patients with proliferative diabetic retinopathy,Proceedings of the National Academy of Sciences, www.pnas.org/cgi/doi/10.1073/pnas.1423765112 Journal reference: Proceedings of the National Academy of Sciences Provided by Johns Hopkins University School of Medicine
Angiopoietin-like 4 is a Potent Angiogenic Factor in Patients with Proliferative Diabetic Retinopathydiabetic retinopathy ( Investigative Ophthalmology & Visual Science April 2014, Vol.55, 5820.) Purpose Proliferative diabetic retinopathy (PDR) is an ischemic retinopathy characterized by retinal neovascularization (NV). In a recent multicenter randomized controlled clinical trial, monthly injection with a monoclonal antibody directed against the potent angiogenic cytokine, vascular endothelial growth factor (VEGF), resulted in a 2/3 reduction - or delay - in the progression to PDR compared to control (sham) treated patients. Although encouraging, this suggests that other factor(s) may drive the development of NV in approximately 1/3 of these patients. Several cytokines have been suggested to promote retinal NV in ischemic retinal disease. We have recently identified angiopoietin-like 4 (ANGPTL4) as a potent angiogenic factor upregulated in animal models of ischemic retinal disease. Here we examine the levels of ANGPTL4 in the aqueous fluid (AF) of patients with diabetic retinopathy. Methods The AF from non-diabetic control (n=60) and diabetic (n=42) patients was collected from consenting patients undergoing cataract or vitrectomy surgery. Levels of VEGF and ANGPTL4 were assessed using an enzyme-linked immunosorbent assay (ELISA). Angiogenic activity was evaluated using an in vitro tubule formation assay. Results ELISA analysis of the AF from diabetic patients revealed 38.5% of PDR patients had VEGF levels below the average level detected in control patients. Surprisingly, 100% of AF from low-VEGF PDR patients remained angiogenic (p<0.001). Using in vitro and in vivo approaches, we identified ANGPTL4 as a potent angiogenic cytokine with increased expression in ischemic retinopathies. Levels of ANGPTL4 were increased by 6.7-fold in PDR compared to control patients (p<0.001). Use of an ANGPTL4 blocking antibody inhibited the angiogenic potential of AF of PDR patients with low-VEGF/high-ANGPTL4 levels. Conclusions Collectively, our results suggest that inhibition of ANGPTL4 may be an effective approach for the treatment of PDR.
Angiopoietin-like protein 4 (ANGPTL4) has been identified as a multifunctional signal protein. It is produced by a variety of tissues, and is secreted into the bloodstream in glycosylated, oligomerized, native and cleaved isoforms to modulate physiological events such as angiogenesis, cell differentiation and the crosstalk between liver, brain, adipose and muscle tissue in lipid and glucose metabolism. In addition, the expression and isoform appearance of ANGPTL4 are modified by the intestinal microbiota. With an eye on an effective strategy to improve health using ANGPTL4, we will focus on: health issues associated with ANGPTL4 expression, including obesity, Type 2 diabetes, cardiovascular diseases and cancer; several modulators of ANGPTL4 of chemical, microbiological, food and host origin; and the correlation of the specific ANGPTL4 isoforms with these modulators and their health effects.
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