Peroxisome proliferator-activated receptor gamma is inhibited by histone deacetylase 4 in cortical neurons under oxidative stress.

摘要

Peroxisome proliferator-activated receptor gamma (PPARgamma) serves an essential protective function in neurons. Although PPARgamma activation is known to reduce brain tissue damage in distinct models of brain diseases, the regulation of PPARgamma activity in neurons is unclear. Here, we report that histone deacetylase 4 (HDAC4) mediates PPARgamma inhibition in cultured cortical neurons under oxidative stress. Our data indicate that HDAC4 physically interacts with PPARgamma and represses PPARgamma transcription activity in cultured cortical neurons. Upon H(2) O(2) treatment, HDAC4 translocates from the cytoplasm to the nucleus, where it inhibits PPARgamma transcription. This inhibition rendered neurons more vulnerable to H(2) O(2) insult. In contrast, knockdown of HDAC4 by introduction of a specific microRNA abolishes the oxidative stress-induced repression of PPARgamma in neurons and also reduces the number of dead neurons induced by H(2) O(2.) Furthermore, over-expression of PPARgamma protects neurons from either HDAC4 over-expression- or H(2) O(2) -induced damage. These data suggest that HDAC4 works to repress PPARgamma transcription and regulates neuronal death by inhibiting PPARgamma pro-survival activity.