Modifications of Chromatin Dynamics Control Smad2 Pathway Activation in Aneurysmal Smooth Muscle Cells

Abstract

Rationale:The activation of the Smad2 signaling pathway is thought to play an important role in human aneurysmal diseases as described by an important body of research. We previously showed that constitutive Smad2 activation is associated with Smad2 mRNA overexpression in aneurysmal vascular smooth muscle cells (VSMCs), which is dependent on epigenetic regulation of the SMAD2 promoter involving histone modifications. However, the underlying molecular mechanisms controlling Smad2 overexpression are currently unknown.Objective: The aim of the present study is to understand the mechanisms regulating the constitutive Smad2 overexpression in VSMCs by identification of the histone-modifying enzymes, transcription factors, and cofactors responsible for Smad2 promoter activation in aneurysmal disease. Methods and Results:This study was performed on medial tissue extracts and primary cultures of VSMCs of human thoracic aneurysms (n=17) and normal thoracic aortas (n=10). Here, we demonstrate that the activation of SMAD2 promoter is driven by the recruitment of a multipartner complex, including the transcription factor p53 and histone acetyltransferases. Remarkably, the transcriptional regulatory network of the SMAD2 promoter is dramatically altered in human aneurysmal VSMCs in vitro and in situ with a switch from Myc-dependent repression of SMAD2 in normal vessel to a p53-dependent activation of SMAD2 in aneurysms. Furthermore, histone acetyltransferases p300 and P300/CBP-associated protein play a major role in SMAD2 promoter activation by acting on histone acetylation, p53 recruitment, and acetylation. Conclusions:

No Beneficial Effect of General and Specific Anti-Inflammatory Therapies on Aortic Dilatation in Marfan Mice

“…Thus increased leukocytes (other than macrophages) and TGF-β/pSmad2 by angiotensin II-induced signaling seems to be the underlying devastating pathway of Marfan syndrome [34]. Recently, a study has demonstrated epigenetic changes in the Smad2 promoter in vascular smooth muscle cells derived from human thoracic aneurysm tissue [35]. This study highlights the important role of Smad2 and TGF-β in thoracic aortic aneurysms.…”

Vascular Smooth Muscle Cell Phenotypic Changes in Patients With Marfan Syndrome

“…38 The finding of high levels of TGF-β in the extracellular medium in Marfan VSMC suggests an autocrine loop, which would explain the chronic activation of the canonical TGF-β signal pathway, as reported in VSMC derived from human abdominal aortic aneurysms. 39 The high levels of active TGF-β could be attributed to the reduced TGF-β reservoir capacity of the defective extracellular assembly of fibrillin-1 microfibrills 40,41 or to epigenetic modifications, 42,43 or both. In any case, they are not caused by the transcriptional increase of TGF-β itself, TGF-β receptors, or other downstream molecular components of the signaling pathway (see Results in the online-only Data Supplement).…”

A functional genomics screen identifies PCAF and ADA3 as regulators of human granzyme B-mediated apoptosis and Bid cleavage

“…47 In contrast to ADA3, PCAF-null mice develop normally, 48 but PCAF is implicated in a number of disease states including arteriosclerosis (including aneurysm formation) and Alzheimer's disease. [49][50][51] A specific PCAF gene polymorphism has also been linked to hepatocellular carcinoma. 52 Malignancies associated with BRCA2 gene mutation may be linked to deregulated PCAF recruitment to target genes, leading to disordered cell division and aneuploidy.…”