Study On The Effect And Mechanism Of Resistin On Lesion Of Coronary Artery In Children With Kawasaki Disease

PART ONERELATIONSHIP BETWEEN RESISTIN AND PATIENTSWITH KAWASAKI DISEASEObjective Kawasaki disease (KD) is an acute febrile disorder withcoronary artery lesions (CAL) that occurs predominantly in infancy andearly childhood. This disease is of great concern to pediatricians, becauseapproximately15%to25%of the patients develop coronary aneurysms.Resistin, a novel adipocyte-derived peptide, belongs to a family ofcysteine-rich secretory proteins. In humans, and it is considered to beinvolved in the pathogenesis of inflammation, coronary artery calcification,atherosclerosis and acute coronary syndrome.This study investigated therelationship between serum levels of resistin and coronary artery aneurysmin patients with KD.Methods Resistin level were measured in166cases with anenzyme-linked immunosorbent assay (ELISA), including4groups: thecontrol group (n=85), and KD with normal coronary arteries (n=41), KD with dilatation (n=31), and KD with coronary aneurysm (n=8). White bloodcells counts (WBC), red blood cells counts (RBC), hemoglobin (HB),Hematocrit (Hct), platelet count, C reactive protein (CRP) and erythrocytesedimentation rate (ESR) were tested in children.Results Levels of resistin were significantly elevated, hemoglobinsignificantly decreased in the group of KD with coronary aneurysm whencompared with the controls or other KD subgroups. Markedly positiverelationship between levels of resistin and CRP and negative relationshipbetween levels of reststin and RBC in patients with KD were found.Conclusions: Resistin and hemoglobin were associated with thedevelopment of coronary aneurysm in children with KD. The up regulationof resistin may be closely linked to upregulation of systemicpro-inflammatory markers in acute KD. PART TWOASSOCIATION OF THE RESISTIN GENE PROMOTERREGION-420C/G POLYMORPHISM WITH KAWASAKIDISEASE CHILDRENObjectives: Kawasaki disease (KD) is a pediatric systemic vasculitisthat often includes coronary artery lesions (CALs). Resistin, a noveladipocyte-derived peptide, has been linked to inflammatory process andcoronary artery disease. The-420C>G polymorphism located in the resistingene (RETN) promoter has recently been suggested to play a potential rolein proinflammatory conditions and cardiovascular disease. However, theassociation between RETN gene polymorphisms and KD is unclear. Thisstudy investigated the association of the RETN promoter polymorphismwith KD and its clinical parameters in Chinese children.Methods: Ninety-one children with KD and115sex-age matchedhealthy subjects were included in this study. We compared patients withfever and four or five of the principal criteria (complete KD, cKD) to theother patients (incomplete KD, iKD). Genotyping of the RETN (-420C>G)promoter polymorphism was performed using MALDI-TOF, and serumresistin levels were estimated using the sandwich enzyme immunoassaymethod.Results: There was no significant difference in RETN (-420C>G)genotypes between KD and control groups. In addition, there was no association between this RETN polymorphism and development of CALs inKD. However, the frequency of the G allele was higher in iKD patients thanin cKD children (P <0.05) due to a significantly increased frequency of theGG genotypes (P <0.05). Serum levels of resistin were significantly higherin KD patients than in controls regardless of the presence of CALs. Amongthe KD patients, serum resistin levels were higher in children with genotypesGG compared to the CC+CG group, but this difference was not significant.Conclusion: The present findings suggest that while resistin may play arole in the pathogenesis of KD, there is no apparent association between KDand the RETN (-420C>G) gene polymorphism in Chinese children.However, the diagnosis of iKD can be supported by the presence of the Gallele and the GG genotypes. PART THREERESISTIN INDUCES MMP-9EXPRESSION VIA MAPKSSIGNALING PATHWAYS IN HUMAN CORONARYARTERY ENDOTHELIAL CELLSObjective: Resistin, firstly reported as an adipocyte-specific hormone,is suggested to be associated with inflammatory and cardiovascular diseases.We recently reported that resistin increased in patients with Kawasakidisease (KD), and were associated with the development of coronaryaneurysm in children with KD; however, the mechanisms underlying thisprocess are currently unknown. Given that matrixmetalloproteinase-9(MMP-9) is the critical link between inflammation andorgan damage in patients with KD. Therefore, we investigated thehypothesis that resistin might regulate the production of MMP-9, the tissueinhibitors of metalloproteinase-1(TIMP-1) and the underlying mechanism.Methods: Human coronary artery endothelial cells (HCAECs) weretreated with resistin. MMP-9and TIMP-1mRNA and protein levels weremeasured with RT-PCR and ELISA. Here, we investigated the roles ofERK1/2, p38MAPK, and JNK pathways for resintin-induced MMP-9production in HCAECs. The phosphorylation of ERK1/2, p38MAPK, andJNK levels were measured by Western blot analysis.Results: Resistin up-regulated production of MMP-9anddown-regulated TIMP-1at both mRNA and protein levels in a time-and concentration-dependent manner. Resistin induced the production ofMMP-9which was attenuated by inhibitors of ERK1/2(U0126), p38MAPK(SB202190), and JNK (SP600125) respectively.Conclusions: Taken together, the ERK1/2, p38MAPK, and JNK thatare involved in MMP-9expression in HCAECs exposed to Resistin havenow been identified. These results suggested a relationship MAPKsresistin-induced cardiovascular disease.