Interleukin-18 knockout mice display maladaptive cardiac hypertrophy in response to pressure overload.

Interleukin (IL)-18 is a cardiotropic proinflammatory cytokine chronically elevated in the serum of patients with cardiac hypertrophy (LVH). The purpose of this study was to examine the role of IL-18 in pressure-overload hypertrophy using wild type (WT) and IL-18 -/- (null) mice. Adult male C57Bl/6 mice underwent transaortic constriction (TAC) for 7days or sham surgery. Heart weight/body weight ratios showed blunted hypertrophy in IL-18 null TAC mice compared to WT TAC animals. Microarray analyses indicated differential expression of hypertrophy-related genes in WT versus IL-18 nulls. Northern, Western, and EMSA analyses showed Akt and GATA4 were increased in WT but unchanged in IL-18 null mice. Our results demonstrate blunted hypertrophy with reduced expression of contractile-, hypertrophy-, and remodeling-associated genes following pressure overload in IL-18 null mice, and suggest that IL-18 plays a critical role in the hypertrophic response.

P2 promoter variants of the hepatocyte nuclear factor 4alpha gene are associated with type 2 diabetes in Mexican Americans.

Common and rare variants of the hepatocyte nuclear factor 4alpha (HNF4A) gene have been associated with type 2 diabetes and related traits in several populations suggesting the involvement of this transcription factor in diabetes pathogenesis. Single nucleotide polymorphisms (SNPs) within a large haplotype block surrounding the alternate P2 promoter, located approximately 45 kb upstream from the coding region, have been investigated in several populations of varying ethnicity with inconsistent results. Additionally, SNPs located within the P1 promoter and coding region have also been inconsistently associated with type 2 diabetes. Characterization of variation across this gene region in Mexican-American populations has not been reported. We therefore examined polymorphisms across the HNF4A gene in a cohort of Mexican-American pedigrees and assessed their association with type 2 diabetes. We observed evidence for association of SNPs in the P2 promoter region with type 2 diabetes (P = 0.003) and its age at diagnosis (P = 0.003). The risk allele frequency (53%) was intermediate to that reported in Caucasian populations (20-27%) and Pima Indians (83%). No other SNPs were associated with either trait. These results support the possibility that a variant in the P2 promoter region of HNF4A, or variants in linkage disequilibrium within this region, contributes to susceptibility to type 2 diabetes in many ethnic populations including Mexican Americans.