New insights in the transcriptional activity and coregulator molecules in the arterial wall.
A number of vascular diseases are associated with abnormal expression of genes that contribute to their pathophysiological and clinical manifestations, but at the same time offer potential therapeutic targets. One of the promising therapeutic approaches targets the pathophysiological pathways leading to aberrant gene activation, namely transcriptional activity and its molecular modulators (agonists, antagonists, coregulators, and nuclear receptors). The transcription factors can be divided into four classes (I-IV) classified by structural elements, like basic leucine zipper (bZIP) or basic helix-loop-helix (bHLH), which mediate their DNA binding activity but also determine the classes of drugs that can affect their activity. For example, statins modulate activation of the class-I transcription factor sterol responsive element-binding protein (SREBP), whose target genes including hydroxyl-methyl-glutaryl acetyl Coenzyme-A (HMG-CoA) reductase, HMG-CoA synthase, and the low-density lipoprotein receptor, all of which are involved in cholesterol and fatty acid metabolism. Similarly, insulin-like drugs target the nuclear receptor peroxisome-proliferator-activator-receptor (PPAR)-gamma (class-II), several anti-inflammatory drugs inhibit activation of nuclear factor kappa B (NFkappaB) (class-IV), while others (e.g. flavopiridol, rapamycin, and paclitaxel) target regulation of cell-cycle proteins. Increased understanding of the genetic and molecular basis of disease (e.g. transcriptional activity and its coregulation) will potentially enhance future diagnosis, treatment, and prevention of vascular diseases.
de Nigris
Filomena
F
Department of Medicine, University of Naples, PO Box 80131, Italy.
Lerman
Lilach O
LO
Napoli
Claudio
C
D001158:Arteries / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000503:physiopathology*; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology; D018390:Gene Targeting; D005809:Genes, Regulator / Q000235:genetics* / Q000502:physiology*; D006801:Humans; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D014158:Transcription, Genetic / Q000235:genetics* / Q000502:physiology*; D015533:Transcriptional Activation; D014652:Vascular Diseases / Q000235:genetics* / Q000503:physiopathology* / Q000628:therapy