Advertisement
Searching for transcriptional regulators of Ang II–induced vascular pathology
Victor J. Dzau1 and Marco Lopez-Ilasaca2
1Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA. 2Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Address correspondence to: Victor J. Dzau, Office of the Chancellor, Duke University Medical Center, Durham, North Carolina 27708, USA. Phone: (919) 684-2255; Fax: (919) 681-7020; E-mail: victor.dzau@duke.edu.
Find articles by Dzau, V. in: JCI | PubMed | Google Scholar
1Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA. 2Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Address correspondence to: Victor J. Dzau, Office of the Chancellor, Duke University Medical Center, Durham, North Carolina 27708, USA. Phone: (919) 684-2255; Fax: (919) 681-7020; E-mail: victor.dzau@duke.edu.
Find articles by Lopez-Ilasaca, M. in: JCI | PubMed | Google Scholar
Published September 1, 2005 - More info
J Clin Invest. 2005;115(9):2319–2322. https://doi.org/10.1172/JCI26384.
© 2005 The American Society for Clinical Investigation
Inflammation and structural remodeling are essential processes mediating vascular responses to humoral and hemodynamic stimuli and have been shown to be involved in the mechanism of vascular disease. Over the past several years, experimental and clinical evidence has demonstrated a key role of Ang II in these processes and that blockade of the renin-angiotensin system (RAS) inhibits vascular inflammation and remodeling and reduces clinical vascular complications. However, an ongoing debate exists with respect to the cardiovascular actions of Ang II and prompts the following questions: (a) Does Ang II have direct in vivo vascular actions independent of its effects on blood pressure? (b) How does Ang II exert its long-term effects in tissue? and (c) Are the multiple Ang II–induced vascular pathologic processes (i.e., inflammation, fibrosis, and proliferation) mediated by common downstream transcription factor(s)?
Certainly, it has been difficult to dissect, in either in vivo or in vitro studies, the direct effect of Ang II on tissue from the indirect effects resulting from its influence on hemodynamics. Clarifying how the effects of Ang II are mediated will be of great clinical relevance, particularly with respect to the question of whether drugs that block RAS (e.g., angiotensin-converting enzyme inhibitors and Ang II receptor blockers) will have any added value beyond their traditional role as blood pressure–lowering agents. Although many in vitro studies have shown that Ang II activates signal transduction pathways, transcriptional activation, and gene expression, these studies have focused on acute experimental conditions, and data explaining the long-term cardiovascular actions of Ang II are lacking. The mechanisms responsible for Ang II activity, from acute to chronic, especially with respect to its effects on transcription regulation, are relatively unknown.
In this context, the study by Zhan et al. in this issue of the JCI (1) provides insight into an important downstream transcription mechanism mediating vascular inflammation and remodeling in response to chronic Ang II infusion. The authors demonstrate that Ets-1 is a critical mediator of vascular remodeling and inflammation in response to Ang II. They show that vascular hyperplasia, perivascular fibrosis, and cardiac hypertrophy are significantly diminished in Ets1–/– mice compared with control mice in response to systemic administration of Ang II. Importantly, these responses occurred independently of any alterations in blood pressure. Furthermore, the induction of 2 known targets of Ets-1, cyclin-dependent kinase inhibitor p21 and plasminogen activator inhibitor–1, by Ang II was markedly blunted in the aorta of Ets1–/– mice compared with wild-type controls. Monocyte chemoattractant protein–1, which had not been previously linked to Ets-1 transcriptional activation, was identified as a novel target for Ets-1. Interestingly, the authors also reported a significant reduction in recruitment of T cells and macrophages to the vessel wall, which supports a critical role for Ets-1 as a transcriptional mediator of vascular inflammation and remodeling in response to Ang II.
-
Programs of transcriptional activation in response to Ang II
Ets-1 is the founder member of the Ets family of transcription factors that specifically recognizes and activates DNA response sequences that contain a GGAA/T core in the promoters of target genes (2). The DNA-binding activity of Ets-1 is controlled by phosphorylation and association with other transcription factors. Phosphorylation by ERK1/2 activates Ets-1, whereas phosphorylation by Ca2+-calmodulin kinase II or myosin light chain kinase inhibits Ets-1 DNA-binding activity. A number of transcription factors have been shown to regulate the transcriptional activity of Ets-1 by modulating Ets-1 DNA-binding affinity, such as acute myeloid leukemia–1, pituitary-specific transacting factor 1, hypoxia-inducible factor 2α, and Pax5 (3). In addition, the interaction of Ets-1 with GATA3, activating transcription factor 2, NF-κB, and Stat5 cooperatively activates target promoters. Ets-1 increases the transcriptional activation of immediate-early gene promoters including a number of genes involved in VSMC growth and proliferation, endothelial activation, and the vascular inflammatory response. Ets-1 also induces the expression of MMP-1, -3, and -9 and urokinase type plasminogen activator; these proteases are known to be involved in extracellular matrix degradation and atherosclerosis progression (4, 5). Ets-1 activation therefore represents a final effector of multiple signaling pathways and components of protein complexes on immediate-early promoters. Indeed, the data reported by Zhan et al. (1) show that Ets-1 is a downstream transcriptional mediator of Ang II–regulated expression of genes involved in the processes of vascular inflammation and remodeling.
Multiple signaling mechanisms potentially link Ang II to Ets-1–dependent transcription (Figure 1). Ang II activates the Ras-MAPK pathway, which in turn induces both the expression and phosphorylation of Ets-1, leading to expression of a number of genes involved in vascular responses. Besides the important role of Ets-1 as an effector of Ang II responses, several other mechanisms of transcriptional control involving nuclear factor of activated T cells, PI3K, AKT, RhoA, or myocardin, acting in concert with or independently of Ets-1, have begun to be characterized (6–8). For example, Ang II induces the binding of serum response factor (SRF) to the specific smooth and cardiac muscle coactivator myocardin; furthermore, the homeodomain protein Prx1 strongly promotes SRF binding to its specific response element after Ang II stimulation. Thus, what has emerged is a multiple-signal transduction system that defines expression of immediate-early genes (via SRF-Ets factors) or tissue-restricted genes (via SRF-myocardin), acting through a combinatorial mechanism of protein-protein interactions in response to Ang II. The observation by Zhan et al. (1) of a decrease in vascular remodeling and inflammation in Ets-1–KO animals in response to Ang II implies that this transcription factor is a critical regulator of multiple pathways that are active in different tissues and, more importantly, identifies Ets-1 as a common denominator of pathways previously considered mechanistically independent.
Figure 1Mechanisms of Ang II_dependent activation of transcriptional programs that lead to changes in vascular function. Ang II activates several groups of transcriptional mechanisms that act in cooperation with Ets-1: (a) Ets-1 binding partners such as activator protein 1 (AP-1), STAT5, nuclear factor of activated T cells (NFAT), GATA, or activating transcription factor 2 (ATF2), which are able to physically bind and regulate Ets-1 activity; (b) KLF5, which is activated in a position upstream of Ets-1; and (c) factors that have been shown to influence vascular function in an Ets-1_independent or _cooperative fashion. The sequence of events that leads to the long-term changes in Ets-1 activation and vascular function in response to Ang II is still undefined. MCP-1, monocyte chemoattractant protein_1; PAI-1, plasminogen activator inhibitor_1; uPA, urokinase type plasminogen activator.
The fact that a network of transcription factors and effector proteins participate in the control of Ang II–dependent vascular remodeling and inflammation raises the question of how these proteins interact with each other and how they coordinate their activities to generate and maintain a specific vascular phenotype. Despite many in vitro observations linking Ang II to a multitude of effectors in VSMC growth and differentiation, there are few reports examining the specific role of these molecules with respect to the in vivo chronic effects of Ang II on the cardiovascular system. Studies in KO mice lacking expression of bradykinin receptor type 2, p66-Shc, PI3Kγ, or Krüppel-like factor 5 (KLF5) have shown that these effectors are critical for vascular responses to Ang II (9–11). However, the hierarchy of responses of these mediators and the place of action of transcription factors such as Ets-1 after the initial Ang II stimulus are unknown. The demonstration by Zhan et al. (1) that Ang II–dependent KLF5 activation occurs upstream of Ets-1 in vivo suggests that Ets-1 is a critical downstream regulator of a complex process that involves a multitude of effectors. The availability of specific KO animals will make it feasible to conduct epistasis analysis to establish the proper order of action of these important factors in Ang II–dependent vascular responses. Furthermore, given its critical role in transcriptional regulation, Ets-1 may be an important therapeutic target for the inhibition of vascular disease.
Copyright © 2024 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)