Ongoing coxsackievirus myocarditis is associated with increased formation and activity of myocardial immunoproteasomes.

A growing body of evidence indicates that viral infections of the heart contribute to ongoing myocarditis and dilated cardiomyopathy. Murine models of coxsackievirus B3 (CVB3)-induced myocarditis mimic the human disease and allow identification of susceptibility factors that modulate the course of viral myocarditis. Susceptible mouse strains develop chronic myocarditis on the basis of restricted viral replication, whereas resistant strains recover after successful virus elimination. In comparative whole-genome microarray analyses of infected hearts, several genes involved in the processing and presentation of viral epitopes were found to be uniformly up-regulated in acutely CVB3-infected susceptible mice compared with resistant animals. In particular, expression of the catalytic subunits LMP2, LMP7, and MECL-1, immunoproteasome proteins important in the generation of major histocom-patibility complex (MHC) class I-restricted peptides, was clearly enhanced in the susceptible host. Increased expression resulted in enhanced formation of immunoproteasomes and altered proteolytic activities of proteasomes in the heart. This was accompanied by a concerted up-regulation of the antigen-presenting machinery in susceptible mice. Thus, we propose that increased formation of immunoproteasomes in susceptible mice affects the generation of antigenic peptides and the subsequent T-cell-mediated immune responses.

A new variant in the human Kv1.3 gene is associated with low insulin sensitivity and impaired glucose tolerance.

CONTEXT: The voltage-gated potassium channel Kv1.3 (KCNA3) is expressed in a variety of tissues including liver and skeletal muscle. In animal models, knockout of Kv1.3 has been found to improve insulin sensitivity and glucose tolerance. OBJECTIVE: We examined whether mutations in the Kv1.3 gene exist in humans and whether they are associated with alterations of glucose homeostasis. DESIGN AND SETTING: We conducted a genotype-phenotype association study at a university hospital. PARTICIPANTS AND METHODS: In 50 nondiabetic subjects, we screened approximately 4.5 kb of chromosome 1 comprising the single exon, the promoter/5'-untranslated region, and the 3'-untranslated region of the human Kv1.3 gene for mutations by direct sequencing. Subsequently, all identified single-nucleotide polymorphisms were analyzed in 552 nondiabetic subjects who underwent an oral glucose tolerance test (OGTT). Of these, 304 had undergone an additional hyperinsulinemic euglycemic clamp. MAIN OUTCOME MEASURES: We assessed postprandial blood glucose during OGTT and insulin sensitivity measured by hyperinsulinemic euglycemic clamp. RESULTS: We identified five single-nucleotide polymorphisms in the promoter region (T-548C, G-697T, A-845G, T-1645C, and G-2069A) with allelic frequencies of the minor allele of 26, 23, 9, 41, and 16%, respectively. The -1645C allele was associated with higher plasma glucose concentrations in the 2-h OGTT (P = 0.03) even after adjustment for sex, age, and body mass index (P = 0.002). In addition, it was associated with lower insulin sensitivity (P = 0.01, adjusted for sex, age, and body mass index). Functional in vitro analysis using EMSA showed differential transcription factor binding to the T-1645C polymorphism. CONCLUSIONS: We show that a variant in the promoter of the Kv1.3 gene is associated with impaired glucose tolerance and lower insulin sensitivity. Therefore, the Kv1.3 channel represents a candidate gene for type 2 diabetes.