In recent years, significant progress has been made in understanding cardiomyocyte differentiation. However, little is known about the regulation of myocyte survival despite the fact that myocyte apoptosis is a leading cause of heart failure. Here we report that transcription factor GATA-4 is a survival factor for differentiated, postnatal cardiomyocytes and an upstream activator of the antiapoptotic gene Bcl-X. An early event in the cardiotoxic effect of the antitumor drug doxorubicin is GATA-4 depletion, which in turn causes cardiomyocyte apoptosis. Mouse heterozygotes for a null Gata4 allele have enhanced susceptibility to doxorubicin cardiotoxicity. Genetic or pharmacologic enhancement of GATA-4 prevents cardiomyocyte apoptosis and drug-induced cardiotoxicity. The results indicate that GATA-4 is an antiapoptotic factor required for the adaptive stress response of the adult heart. Modulation of survival͞apoptosis genes by tissue-specific transcription factors may be a general paradigm that can be exploited effectively for cell-specific regulation of apoptosis in disease states.transcription ͉ apoptosis ͉ Bcl-X ͉ doxorubicin ͉ ␣1-adrenergic receptors

We investigated whether serum titers of interleukin 10 (IL-10), a cytokine known to shift lymphocyte responses towards humoral immunity, reflect disease activity in systemic lupus erythematosus (SLE). Sera from 72 SLE patients, 25 RA patients and 30 healthy controls were tested for IL-10 by ELISA. Low titers of IL-10 were detected in the serum of 37.5% of SLE patients and in 24% of RA patients but in only 3% of healthy controls. Interestingly, serum IL-10 titers in SLE patients were positively correlated with the SLE Disease Activity Index (SLEDAI) and with anti-DNA antibody titers, but negatively with complement fraction C3 levels. These results indicate that serum IL-10 values reflect SLE disease activity and suggest that overexpression of IL-10 might play a pathogenic role in severe lupus disease.

In humans, congenital heart defects occur in 1-2% of live birth, but the molecular mechanisms and causative genes remain unidentified in the majority of cases. We have uncovered a novel transcription pathway important for heart morphogenesis. We report that KLF13, a member of the Krü ppel-like family of zinc-finger proteins, is expressed predominantly in the heart, binds evolutionarily conserved regulatory elements on cardiac promoters and activates cardiac transcription. KLF13 is conserved across species and knockdown of KLF13 in Xenopus embryos leads to atrial septal defects and hypotrabeculation similar to those observed in humans or mice with hypomorphic GATA-4 alleles. Physical and functional interaction with GATA-4, a dosage-sensitive cardiac regulator, provides a mechanistic explanation for KLF13 action in the heart. The data demonstrate that KLF13 is an important component of the transcription network required for heart development and suggest that KLF13 is a GATA-4 modifier; by analogy to other GATA-4 collaborators, mutations in KLF13 may be causative for congenital human heart disease.