Inhibitor of DNA Binding Protein 3 (ID3) and Nuclear Respiratory Factor 1 (NRF1) Mediated Transcriptional Gene Signatures are Associated with the Severity of Cerebral Amyloid Angiopathy.

Cerebral amyloid angiopathy (CAA) is a degenerative vasculopathy. We have previously shown that transcription regulating proteins- inhibitor of DNA binding protein 3 (ID3) and the nuclear respiratory factor 1 (NRF1) contribute to vascular dysregulation. In this study, we have identified sex specific ID3 and NRF1-mediated gene networks in CAA patients diagnosed with Alzheimer's Disease (AD). High expression of ID3 mRNA coupled with low NRF1 mRNA levels was observed in the temporal cortex of men and women CAA patients. Low NRF1 mRNA expression in the temporal cortex was found in men with severe CAA. High ID3 expression was found in women with the genetic risk factor APOE4. Low NRF1 expression was also associated with APOE4 in women with CAA. Genome wide transcriptional activity of both ID3 and NRF1 paralleled their mRNA expression levels. Sex specific differences in transcriptional gene signatures of both ID3 and NRF1 were observed. These findings were further corroborated by Bayesian machine learning and the GeNIe simulation models. Dynamic machine learning using a Monte Carlo Markov Chain (MCMC) gene ordering approach revealed that ID3 was associated with disease severity in women. NRF1 was associated with CAA and severity of this disease in men. These findings suggest that aberrant ID3 and NRF1 activity presumably plays a major role in the pathogenesis and severity of CAA. Further analyses of ID3- and NRF1-regulated molecular drivers of CAA may provide new targets for personalized medicine and/or prevention strategies against CAA.

Molecular basis of the association between transcription regulators nuclear respiratory factor 1 and inhibitor of DNA binding protein 3 and the development of microvascular lesions.

The prognosis of patients with microvascular lesions remains poor because vascular remodeling eventually obliterates the lumen. Here we have focused our efforts on vessel dysfunction in two different organs, the lung and brain. Despite tremendous progress in understanding the importance of blood vessel integrity, gaps remain in our knowledge of the underlying molecular factors contributing to vessel injury, including microvascular lesions. Most of the ongoing research on these lesions have focused on oxidative stress but have not found major molecular targets for the discovery of new treatment or early diagnosis. Herein, we have focused on elucidating the molecular mechanism(s) based on two new emerging molecules NRF1 and ID3, and how they may contribute to microvascular lesions in the lung and brain. Redox sensitive transcriptional activation of target genes depends on not only NRF1, but the recruitment of co-activators such as ID3 to the target gene promoter. Our review highlights the fact that targeting NRF1 and ID3 could be a promising therapeutic approach as they are major players in influencing cell growth, cell repair, senescence, and apoptotic cell death which contribute to vascular lesions. Knowledge about the molecular biology of these processes will be relevant for future therapeutic approaches to not only PAH but cerebral angiopathy and other vascular disorders. Therapies targeting transcription regulators NRF1 or ID3 have the potential for vascular disease-modification because they will address the root causes such as genomic instability and epigenetic changes in vascular lesions. We hope that our findings will serve as a stimulus for further research towards an effective treatment of microvascular lesions.