doi: 10.1161/01.RES.0000147313.80351.92
© 2004 American Heart Association, Inc.
Editorials |
Blood Pressure Control Goes Nuclear
From the Carolina Cardiovascular Biology Center and Departments of Medicine, Pharmacology, and Department of Cell and Developmental Biology, University of North Carolina, Chapel Hill, NC.
Correspondence to Cam Patterson, MD, Director, Carolina Cardiovascular Biology Center, University of North Carolina at Chapel Hill, 8200 Medical Biomolecular Research Building, Chapel Hill, NC 27599-7126. E-mail cpatters{at}med.unc.edu
See related article, pages 902–910
Key Words: endothelium • DNA repair • hypertension • nitric oxide
The control of blood pressure is regulated with extreme precision, and requires integration of information from the central nervous system, the kidneys, the vasculature, and the heart. Salt and water balances, sympathetic activity, arterial stiffness, and the tone of resistance vessels determine the chronic regulation of intravascular pressure. It is a standard experiment for physicians-in-training to manipulate these activities using classical physiological techniques and observe the homeostatic mechanisms that return blood pressure to its normal levels. Given the many controls that exist to maintain blood pressure within a narrow and appropriate range, it is all the more remarkable that clinical hypertension is as common as it is, affecting more than 50 million Americans and 75% of the population older than 65 years of age.
The paracrine and endocrine mechanisms that regulate blood pressure are now reasonably well understood, and indeed provide the pharmacological basis for most antihypertensive therapies. In contrast, the intracellular events that tune blood pressure are less well characterized. In particular, nuclear events that control blood pressure are not well known. This is a major gap in our understanding of the problem insofar as long-term changes in gene regulation are a likely proximate cause of the systematic events that result in chronic hypertension. A report in this issue of Circulation Research by Irani and colleagues,1 which clearly defines a role for the multifunctional nuclear protein apurinic/apyrimidinic endonuclease (APE1, also known as redox factor-1) in chronic regulation of vascular tone in vivo, represents an important step toward understanding how nuclear proteins may integrate diverse signals to tune the genetic program that regulates blood pressure.
APE1 is a multifunctional protein (Figure, A). It contains tandem cysteine residues within its amino terminus that exert a reducing activity that is responsible for regulating redox-sensitive transcription factors in the nucleus such as AP-1 and p53.2,3 The carboxyl terminus of APE1 contains an endonuclease activity that is required for repair of DNA that is damaged because of a variety of factors, including oxidative damage.4 In addition, APE1 participates directly in regulation of gene transcription, at least in part through associations with histone deacetylases.5 In the present report, the investigators make the remarkable observation that mice lacking only one of the two APE1 alleles (APE1+/–) have markedly elevated blood pressures, as determined by intraarterial measurements. This phenotype is accompanied by decreased basal nitric oxide production in arteries from APE1+/– mice, an effect that partially accounts for abnormally enhanced contractile responses in these mice.
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This unexpected set of observations led the investigators to explore a role for APE1 in regulation of nitric oxide synthase activity. Within the vascular endothelium, endothelial nitric oxide synthase (eNOS) activity is affected by levels of expression and also by well-characterized signaling pathways that activate eNOS. Expression of eNOS cannot be the major determinant of the hypertensive phenotype of APE1+/– mice, because eNOS levels are actually increased in the vessels of these mice in spite of their impaired ability to generate nitric oxide. The effect seems to be at the level of eNOS activation. Based on the data presented in this report it is reasonable to conclude that this is due in part to upregulation of H-Ras, which lies upstream of the phosphoinositide-3 kinase/Akt kinase pathway that potently activates eNOS.
The investigators conclude that increased Akt activation occurs via APE1-dependent upregulation of H-Ras expression, although the effect on H-Ras is modest and other activities of APE1 may be impacting the activity of eNOS in a synergistic way. Nevertheless, these are important mechanistic observations that provide a basis for understanding why mice lacking one copy of the APE1 gene develop chronic hypertension. However, it is critical to emphasize that APE1 may coordinate nuclear events that impact vascular reactivity and blood pressure control through multiple mechanisms in addition to its effects on nitric oxide generation.
It is important to keep in mind that homeostatic principles make it difficult for any single intervention to chronically alter blood pressure. This is particularly true in rodents, which are relatively resistant to the hypertensive effects of chronic catecholamine administration or to the antihypertensive actions of drugs such as angiotensin-converting enzyme inhibitors.6,7 The impressive cardiovascular phenotypes of APE1+/– mice argue that APE1 regulates vascular tone at several different steps. What might these be? The cysteine residues within the amino terminus of APE1 are required for redox-dependent activation of transcription factors within the nucleus,3 and these residues also provide protection against reactive oxygen species in endothelial cells that can increase vascular tone by reacting with nitric oxide.8 This redox activity is required for APE1-dependent protection against endothelial cell death in response to noxious stimuli such as hypoxia and cytokines,9 so APE1 may be particularly well suited for maintaining endothelial function in vivo.
APE1 is also a well-characterized base-excision repair enzyme for oxidatively damaged DNA.4 How this activity might relate to blood pressure control is unclear and indeed an interesting topic for further consideration. It is known that damaged DNA accumulates in human vascular lesions,10,11 and that oxidative events that trigger DNA damage are closely linked to hypertension and atherosclerosis.12 It is logical to hypothesize that by protecting against accumulation of DNA damage, APE1 may preserve endothelial function, and that reduction of APE1 activity may in turn permit DNA damage to accumulate and genetically "lock" cells in maladaptive programs that allow hypertension to persist.
APE1 has a third and less well-appreciated activity as a direct transcriptional regulator. This activity was first demonstrated in studies of parathyroid hormone mRNA expression and it is interesting from the perspective of blood pressure control that the transcriptional activity of APE1 is calcium-dependent.13 Calcium-dependent activation of APE1 occurs at least in part via regulated acetylation of APE1 by the transcriptional coactivator p300, which allows APE1 to bind "negative calcium response elements" and suppress gene expression.5 Given the role of calcium ions in regulating vascular tone, it is easy to imagine that APE1 may participate in transcriptional programs that determine the expression of master genes involved in blood pressure regulation. Indeed, APE1 was recently found to be a necessary component of a calcium-dependent transcriptional suppression complex that inhibits renin expression.14 Although Irani and colleagues did not measure plasma renin activity in their mice, a necessary transcriptional effect of APE1 on regulatory genes such as renin would be entirely consistent with the phenotypes of APE1+/– mice observed in this report.
It is too soon to know exactly how APE1 contributes to regulation of blood pressure, in addition to the effects on nitric oxide synthase activity that have been elegantly defined by Irani and colleagues. However, it is tempting to speculate that APE1 may play an integrative role in maintaining vascular tone. Through its dual activities as a redox regulator and DNA damage-repair enzyme, APE1 may serve as a sensor of the cellular environment that would ultimately prepare blood vessels to respond through alterations in vascular tone. The downstream consequences of this activity would be calcium-dependent regulation of master control genes such as nitric oxide synthase, renin, and perhaps others that tune vascular responses. Such a model would postulate that imbalances among the different functions of APE1 could lead to chronic hypertension, particularly if APE1 functions are competitive with one another (Figure, B). For example, in situations where APE1 is enlisted to act as a DNA repair enzyme, its ability to suppress the expression of genes such as renin would likely be diminished, and hypertension would ensue. Such a scenario could be operative in aging-associated hypertension, given the association between aging and increased DNA damage.15,16 In this regard, it would be very interesting to carefully examine the blood vessels of APE1+/– mice for sclerosis, changes in compliance, and other indices that might suggest an accelerated vascular aging phenotype.
Clearly, the results of the present report by Irani and colleagues open the door for a more thorough investigation of how APE1 plays such a powerful role in blood pressure regulation. The observation that APE1+/– mice develop chronic hypertension serves as an invitation to characterize the phenotypes of these mice more thoroughly. In particular, it will be interesting to dissect the mechanisms by which their blood pressure is dysregulated in more detail, and to determine whether these mice are more prone to particularly sequelae of hypertension, such as nephrosclerosis and atherosclerosis. In addition, these studies provide a rationale for a comprehensive evaluation of a possible link between DNA damage repair mechanisms and chronic blood pressure regulation. Finally, it will be worthwhile to consider whether APE1 plays a role in the pathogenesis of human hypertension. Five common polymorphisms exist within the human APE1 gene,17 so it is easy to imagine that differences in the activity of APE1 because of genetic variations or age-associated changes in APE1 function may contribute to clinical hypertension. The present report offers the opportunity to reformulate the question of how hypertension develops and is sustained chronically, and whether major regulators of blood pressure control exist in unsuspected locations, such as the nucleus.
Acknowledgments
Work in the author’s laboratory is supported by NIH grants GM61728, HL65619, AG02482, and HL61656. C.P. is an Established Investigator of the American Heart Association and a Burroughs Wellcome Fund Clinical Scientist in Translational Research. The graphical contributions of Rob Lineberger to this editorial are greatly appreciated.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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Related Article:
- Apurinic/Apyrmidinic Endonuclease 1 Regulates Endothelial NO Production and Vascular Tone
- Byeong Hwa Jeon, Gaurav Gupta, Young Chul Park, Bing Qi, Azeb Haile, Firdous A. Khanday, Yan-Xia Liu, Jin-Man Kim, Michitaka Ozaki, Anthony R. White, Dan E. Berkowitz, and Kaikobad Irani
Circ. Res. 2004 95: 902-910.[Abstract] [Full Text] [PDF]
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