Diabetic Microangiopathy in Ischemic Limb Is a Disease of Disturbance of the Platelet-Derived Growth Factor-BB/Protein Kinase C Axis but Not of Impaired Expression of Angiogenic Factors

Abstract

Abstract-Diabetic foot is caused by microangiopathy and is suggested to be a result of impaired angiogenesis. Using a severe hindlimb ischemia model of streptozotocin-induced diabetic mice (STZ-DM), we show that diabetic foot is a disease solely of the disturbance of platelet-derived growth factor B-chain homodimer (PDGF-BB) expression but not responses of angiogenic factors. STZ-DM mice frequently lost their hindlimbs after induced ischemia, whereas non-DM mice did not. Screening of angiogenesis-related factors revealed that only the expression of PDGF-BB was impaired in the STZ-DM mice on baseline, as well as over a time course after limb ischemia. Supplementation of the PDGF-B gene resulted in the prevention of autoamputation, and, furthermore, a protein kinase C (PKC) inhibitor restored the PDGF-BB expression and also resulted in complete rescue of the limbs of the STZ-DM mice. Inhibition of overproduction of advanced-glycation end product resulted in dephosphorylation of PKC-␣ and restored expression of PDGF-BB irrespective of blood sugar and HbA1c, indicating that advanced-glycation end product is an essential regulator for PKC/PDGF-BB in diabetic state.

Cardiac Protection by Basic Fibroblast Growth Factor from Ischemia/Reperfusion-Induced Injury in Diabetic Rats

“…It is known that antioxidant and angiogenic action of FGF are mediated by signaling pathways that involves in several other kinases, such as Akt, extracellular signal-regulated kinase (Erk1/2), and vascular endothelial growth factor (VEGF). [13][14][15][16]45) As mentioned above, diabetes impairs several antioxidants and growth factors, [17][18][19][20][21] administration of single exogenous rhbFGF alone is unable to overcome all these defectives, and consequently offered a slightly less protection in diabetic rats as compared to that in non-diabetic rats. Therefore, combination of bFGF with other growth factors may be a potential approach to optimize the protective effect of bFGF against I/R-induced cardiac injury 46) even under diabetic conditions, which will be warranty in the future studies.…”

“…[13][14][15][16] For instance, diabetes inhibited the expression, and also induced glycosylation of several growth factors, including endogenous FGF. [17][18][19][20][21] Decreased serum levels of bFGF with other growth factors were found to increase cardiovascular events (including infarction, revascularization, stroke and peripheral vascular disease) in diabetic patients. 22) Supplementation of exogenous FGFs attenuated diabetes-caused neuronal and gastric tissue damage.…”

VEGF-A i PDGF-BB — czynniki angiogenne a stopień zaawansowania zespołu stopy cukrzycowej

“…The accumulation of AGEs (advanced glycation end products) was associated with reduced PDGF-B expression. The supplementation of PDGF-B gene restored normal level of PDGF-BB in the tissue and protected against ischaemic limb autoamputation [27].…”

Antagonism of VEGF by Genetically Engineered Dendritic Cells Is Essential to Induce Antitumor Immunity against Malignant Ascites

“…Real-time monitoring of the amplification of target genes and quantification of gene expression levels were done by a Sequence Detection System (model 7000; Applied Biosystems), according to the manufacturer's instructions for TaqMan methods (15 0 . The expression level of the target genes was standardized by the glyceraldehydes-3-phosphate dehydrogenase level in each sample and was expressed as fold increase over the control level.…”