Disruption of vascular homeostasis in patients with Kawasaki disease: Involvement of vascular endothelial growth factor and angiopoietins

Abstract

Objective. In Kawasaki disease (KD), a pediatric vasculitis of medium-sized arteries, the coronary arteries are most commonly affected. Angiopoietins and vascular endothelial growth factor (VEGF) play an important role in maintaining vascular homeostasis. Recently, we identified ANGPT1 and VEGFA as susceptibility loci for KD. This study was undertaken to fine-map these associations and to gain further insight into their role in this vasculitis of unknown etiology to further the search for improved diagnostic and therapeutic options.Methods. A total of 292 single-nucleotide polymorphisms (SNPs) located in VEGF and ANGPT and their receptors were genotyped in 574 families, including 462 trios. For replication, 123 cases and 171 controls were genotyped.Results. A significant association with KD susceptibility was observed with 5 SNPs in the ANGPT1 gene (most significantly associated SNP ؉265037 C>T; P combined ‫؍‬ 2.3 ؋ 10 ؊7 ) and 2 SNPs in VEGFA (most significantly associated SNP rs3025039; P combined ‫؍‬ 2.5 ؋ 10 ؊4 ). Both ANGPT1 ؉265037 C>T and VEGFA rs3025039 are located in 3 regulatory regions at putative transcription factor binding sites. We observed significantly down-regulated transcript levels of angiopoietin 1 (Ang-1) in patients with acute KD compared to patients with convalescent KD. In patients with acute KD, high serum protein levels of VEGF and Ang-2 were observed compared to patients with convalescent KD and to both controls with and controls without fever. Immunohistochemistry demonstrated VEGF and angiopoietin expression in the coronary artery wall in autopsy tissue. Conclusion. Our data support the hypothesis that dysregulation of VEGF and angiopoietins contributes to the disruption of vascular homeostasis in KD.Kawasaki disease (KD) is a systemic vasculitis of the medium-sized arteries, predominantly affecting the coronary arteries. KD affects mainly children younger than 5 years. The clinical and laboratory features observed in KD patients suggest an infectious trigger, but none has been identified. A genetic predisposition is suggested by the difference in incidence between children of Asian ethnicity and those of Caucasian ethnicity, which is sustained in those who migrate to countries with lower incidence, and the increased incidence in siblings and parents of children with KD (1,2).In general, it is proposed that an unknown inflammatory stimulus initiates a cascade of events that

Pro‐inflammatory cytokine single nucleotide polymorphisms in Kawasaki disease

“…The TNF‐α G allele at ‐308 has shown association with increased KD prevalence in several separate studies and also in a systematic review . However, our study failed to demonstrate such association in an Iranian population.…”

miR-27b Suppresses Endothelial Cell Proliferation and Migration by Targeting Smad7 in Kawasaki Disease

“…Wang et al reported that serum Th1 and Th2 cytokine expression were higher in KD patients with coronary artery lesions (CALs) than those without CALs [26]. Breunis et al hypothesized that genetic variation may be involved in the development of CALs [27]. Another study revealed that peripheral blood mononuclear cell miR-93 may regulate the expression of vascular endothelial growth factor A and is involved in the pathogenesis of arteritis in acute KD [28].…”

Kawasaki disease: a matter of innate immunity

“…VEGFA , KDR and ANGPT1 have also been reported to be associated with KD. These data suggest that dysregulation of vascular endothelial growth factor (VEGF) and angiopoietins contributes to the disruption of vascular homeostasis in KD .…”