ABSTRACT
Pain perception has evolved as a warning mechanism to alert organisms to tissue damage and dangerous environments. In humans, however, undesirable, excessive or chronic pain is a common and major societal burden for which available medical treatments are currently suboptimal. New therapeutic options have recently been derived from studies of individuals with congenital insensitivity to pain (CIP). Here we identified 10 different homozygous mutations in PRDM12 (encoding PRDI-BF1 and RIZ homology domain-containing protein 12) in subjects with CIP from 11 families. Prdm proteins are a family of epigenetic regulators that control neural specification and neurogenesis. We determined that Prdm12 is expressed in nociceptors and their progenitors and participates in the development of sensory neurons in Xenopus embryos. Moreover, CIP-associated mutants abrogate the histone-modifying potential associated with wild-type Prdm12. Prdm12 emerges as a key factor in the orchestration of sensory neurogenesis and may hold promise as a target for new pain therapeutics.
Subject(s)
Carrier Proteins/genetics , Nerve Tissue Proteins/genetics , Pain Perception , Animals , COS Cells , Carrier Proteins/metabolism , Chlorocebus aethiops , Consanguinity , Female , Genetic Association Studies , Hereditary Sensory and Autonomic Neuropathies/genetics , Humans , Male , Mutation , Nerve Tissue Proteins/metabolism , Neurogenesis , Nociceptors/metabolism , Pain Insensitivity, Congenital/genetics , Pedigree , Polymorphism, Single Nucleotide , Xenopus laevisABSTRACT
Enhancement of the generation of nitric oxide (NO) and vascular endothelial growth factor (VEGF) are suggested to prevent restenosis after angioplasty. Accordingly, we tested whether the local delivery of L-arginine (L-Arg), a substrate for NO generation and the VEGF gene, alone or in combination, can influence neointima formation in hypercholesterolemic rabbits. Balloon injury of the iliac arteries was performed in 24 New Zealand White rabbits fed a 1% cholesterol diet for 3 weeks followed by a local infusion of: (1) pSG5VEGF165 plasmid alone (1000 microg); (2) pSG5VEGF165 (1000 microg) with L-Arg (800mg); (3) L-Arg (800mg) alone; and (4) L-Arg (800 mg) with naked pSVbeta-gal plasmid (1000 microg). The animals were kept on the hypercholesterolemic diets for a further 28 days, when vessels were taken for morphometric analysis and immunocytochemistry. Endogenous rabbit VEGF concentration in the plasma increased significantly at 7 days after injury (17.06 +/- 1.57 vs 23.01 +/- 1.9 pg/ml; p < 0.02) and remained elevated for up to 28 days (28.46 +/- 5.24; p < 0.01). Injured arteries exhibited strong immunocytochemical staining for rabbit VEGF. Rabbits that received a VEGF gene transfer revealed more prominent neointima formation, whereas treatment with L-Arg was associated with significantly less intimal thickness (p < 0.05). Local transfer of the VEGF gene does not inhibit neointima formation in hypercholesterolemic rabbits. Our results suggest that VEGF gene therapy applied locally in atherosclerotic arteries may not be beneficial.