doi: 10.1161/01.HYP.0000126285.39029.de
(Hypertension. 2004;43:1173.)
© 2004 American Heart Association, Inc.
Editorial Commentaries |
Gene Therapy and Heme Oxygenase Coming of Age
From the Department of Physiology, Medical College of Wisconsin, Milwaukee.
Correspondence to Richard J. Roman, Department of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53005. E-mail rroman{at}mcw.edu
The article by Yang et al1 in this issue of Hypertension is noteworthy in that it makes significant contributions in 2 areas. First, the authors describe an approach using retroviral constructs to achieve long-term (up to 5 months) expression of a human heme-oxygenase 1 (HO-1) gene in the liver, kidney, and vasculature of rats in vivo. They also demonstrated that they could knockdown endogenous HO-1 activity in rats by administration of a retrovirus containing a rat HO-1 antisense construct. The second major advance in this study is that it provides new information that further highlights the importance of the HO/CO system as a key modulator of vascular tone in vivo. They found that overexpression of the human HO-1 gene in the rat attenuates the pressor response to intravenous administration of angiotensin II and that knockdown of endogenous HO-1 activity potentiates the pressor response to angiotensin II.
Gene Therapy Approaches in Hypertension Research
The completion of the sequencing of the human, rat, and mouse genomes now provides an unprecedented opportunity for the discovery of new genes, pathways, and drug targets for the treatment of hypertension and associated end-organ damage. Unfortunately, an examination of the publicly available genome databases (eg, LocusLink, Online Medelian Inheritance in Man [OMIM], the Human Genome Organization [HUGO], and the Genome Database [GDB]) reveals that only 
5000 of the 30 000 predicted human genes have any inferred function. The challenge is now to attach function to the genome and to identify the genes and pathways involved in human disease. Most of the progress to date has been generated using targeted gene knockout in mice.2–4 While this approach has proven to be extremely valuable to confirm the actions of known genes, it has been less effective in defining the function of the newly discovered genes. One of the problems is that it is difficult to develop phenotyping protocols broad enough to identify all the functional consequences associated with knockout of a gene without prior knowledge of the function or organ systems to study. The gene knockout approach has also run into problems with the failure to produce obvious phenotypes and genomic background effects.5 The emergence of adenoviral vectors for transient gene therapy6 and now retroviral vectors to achieve long-term expression of constructs in vivo as described in this study1 offers a number of advantages for future functional genomics studies. First, viral constructs can be produced to enhance or knockdown the expression of any gene. Viral-driven gene therapy can be applied to any species. This is especially relevant to workers using rats, in which a large number of well characterized inbred models of hypertension and associated end-organ damage are available. Given these advantages, it is likely that viral-driven gene therapy approaches as well as other related knockdown techniques (RNAi) will become as commonplace as traditional pharmacological tools to unravel the contribution of different genes and pathways to the pathogenesis of hypertension and other complex diseases.
Heme Oxygenase/Carbon Monoxide in the Control of Vascular Tone
The other major contribution of the study by Yang et al1 is that it emphasizes the critical role of HO and CO in the control of vascular tone. In the past 5 years, this field has exploded; nearly 500 articles have been published this year alone. It is now apparent that HO is expressed in blood vessels and tissues throughout the body and that CO serves as an important endogenous mediator of vascular tone7–11. It is a potent vasodilator that has multiple effects on vascular smooth muscle. These actions include activation of guanylyl cyclase, 9,11direct activation of K+ channels,11 inhibition of the formation of NO12 and P450 metabolites of arachidonic acid, 10,13 stimulation of the formation of prostacyclin, 14 and downregulation of the expression of CYP4A and cyclooxygenase 2 enzymes.13 The study by Yang et al1 indicates that overexpression of HO attenuates the pressor response to angiotensin II. This finding suggests that angiotensin II increases the production of CO and that CO modulates the vasoconstrictor response to angiotensin II. More work is needed to understand the mechanisms by which HO-1 and CO alter the vasoconstrictor response to angiotensin II. CO could be formed and act at the level of vascular smooth muscle cells to directly oppose the actions of angiotensin II. However, because HO-1 is highly expressed in the brain and the nervous system, it is just as likely that locally generated CO may influence baroreflex responses to exogenous administration of angiotensin II. Regardless of the mechanism involved, this article is important in that it further defines the role of HO and CO in the control of vascular tone and the regulation of blood pressure.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
References
1. Yang L, Quan S, Nasjletti A, Laniado-Schwartzman M, Abraham N. Heme oxygenase-1 gene expression modulates angiotensin II induced increase in blood pressure. Hypertension. 2004; 43: 1221–1226.
2. Takahashi N, Smithies O. Gene targeting approaches to analyzing hypertension. JASN. 1999; 10: 1598–1605.
3. Zambrowicz BP, Sands AT. Knockouts model the 100 best-selling drugs-will they model the next 100? Nature Rev Drug Discovery. 2003; 2: 38–51.[CrossRef][Medline] [Order article via Infotrieve]
4. van der Weyden L, Adams DJ, Bradley A. Tools for targeted manipulation of the mouse genome. Physiol Genomics. 2002; 11: 133–164.
5. Wolfer DP, Crusio WE, Lipp HP. Knockout mice: simple solutions to the problems of genetic background and flanking genes. Trends Neurosci. 2002; 25: 336–340.[CrossRef][Medline] [Order article via Infotrieve]
6. Francis SC, Raizada MK, Mangi AA, Melo LG, Dzau VJ, Vale PR, Isner JM, Losordo DW, Chao J, Katovich MJ, Berecek KH. Genetic targeting for cardiovascular therapeutics: are we near the summit or just beginning the climb? Physiol Genomics. 2001; 7: 79–94.
7. Johnson RA, Lauesa M, Askari B, Abraham NG, Nasjletti. A heme oxygenase product presumably carbon monoxide, mediate a vasodepressor function in rats. Hypertension. 1995; 25: 166–169.
8. Kaide JI, Zhang F, Wei Y, Jiang H, Yu C, Wang WH, Balazy M, Abraham NG, Nasjletti A. Carbon monoxide of vascular origin attenuate the sensitivity of renal arterial vessels to vasoconstrictors. J Clin Invest. 2001; 107: 1163–1171.[Medline] [Order article via Infotrieve]
9. Ndisang JF, Zhoa W, Wang R. Selective regulation of blood pressure by heme oxygenase-1 in hypertension. Hypertension. 2002; 40: 315–321.
10. Coceani F, Kelsey L, Sedlitz E. Carbon-monoxide-induced relaxation of the ductus arteriosus in the lamb: Evidence against a primary role for guanylyl cyclase. Br J Pharmacol. 1996; 118: 1689–1696.[Medline] [Order article via Infotrieve]
11. Wang R, Wang Z, Wu L, Hanna ST, Peterson-Wakeman R. Reduced vasorelaxant effect of carbon monoxide in diabetes and the underlying mechanisms. Diabetes. 2001; 50: 166–174.
12. Johnson FK, Durante W, Peyton KJ, Johnson RA. Heme oxygenase inhibitor restores nitric oxide function in dahl rats. Hypertension. 2003; 41: 149–155.
13. Bortros FT, Laniado-Schwartzman M, Abraham NG. Regulation of cyclooxygenase- and cytochrome p450-derived eicosanoids by heme oxygenase in the rat kidney. Hypertension. 2002; 39: 639–644.
14. Rodriguez F, Kemp R, Balazy M, Nasjletti A. Effects of exogenous heme on renal function: role of heme oxygenase and cyclooxygenase. Hypertension. 2003; 42: 680–684.
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