Abstract
Somatic gene delivery approaches have received wide attention as a new technique for studying gene expression and as a potential therapeutic tool in treating both inherited and acquired diseases. Recent studies using nonviral and viral vectors have shown great promise for gene therapy in hypertensive diseases. Potential targets for prospective gene therapy in hypertension include vasopressor renin-angiotensin system components and a number of vasodilator polypeptides such as tissue kallikrein-kinin, atrial natriuretic peptide, adrenomedullin and nitric oxide synthase.
Antisense inhibition with oligonucleotides or cDNAs encoding renin, angiotensinogen, angiotensin-converting enzyme and angiotensin receptors has been shown to cause a prolonged blood pressure reduction in spontaneously hypertensive rats. To evaluate the therapeutic potential of vasodilator proteins or peptides in high blood pressure, we delivered the genes encoding human tissue kallikrein, atrial natriuretic peptide, nitric oxide synthase, and adrenomedullin into hypertensive rat models and showed that a single injection resulted in a significant and sustained reduction of blood pressure for several weeks. The potency and duration of blood pressure reduction depends on the dose and the promoter of the gene administered, age and sex of the hypertensive animals as well as the vehicle used for gene delivery. Somatic gene transfer of human tissue kallikrein or atrial natriuretic peptide not only attenuated hypertension but also exerted a protective effect against salt-induced renal damage and cardiac hypertrophy in Dahl salt-sensitive rats after high salt loading.
These results suggest that the application of antisense inhibition of vasopressors, or gene delivery of vasodepressors for gene therapy, may have potential in treating human hypertension, and cardiovascular and renal disorders.
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References
Wilson PW. An epidemiologic perspective of systemic hypertension, ischemic heart disease, and heart failure. Am J Cardiol 1997; 80 (9B Special Issue 51): J3–8
Proven Strategies in Prevention and Treatment of Hypertension meeting: 1996 Oct 24–25; Turnberry Isle Resort, Aventura (FL)
Phillips MI, Gyurko R. Antisense oligonucleotides: new tools for physiology. News Physiological Sci 1997; 12: 99–105
Chao J, Chao L. Experimental kallikrein gene therapy in hypertension, cardiovascular and renal diseases. Pharmacol Res 1997; 35(6): 517–22
Linz W, Wiemer G, Gohlke P, et al. Contribution of kinins to the cardiovascular actions of angiotensin-converting enzyme inhibitors. Pharmacol Rev 1995; 47: 25–49
Wielbo D, Simon A, Phillips MI, et al. Inhibition of hypertension by peripheral administration of antisense oligodeoxynucleotides. Hypertension 1996; 28: 147–51
Lu D, Yang H, Raizada MK. Attenuation of ANG II actions by adenovirus delivery of AT1 receptor antisense in neurons and SMC. Am J Physiol 1998; 274: H719–27
Fukamizu A, Sugimura K, Takimoto E, et al. Chimeric renin-angiotensin system demonstrates sustained increase in blood pressure of transgenic mice carrying both human renin and human angiotensinogen genes. J Biol Chem 1993; 268: 11617–21
Wielbo D, Sernia C, Gyurko R, et al. Antisense inhibition of hypertension in the spontaneously hypertensive rat. Hypertension 1995; 25: 314–9
Tanimoto K, Sugiyama F, Goto Y, et al. Angiotensinogen-deficient mice with hypotension. J Biol Chem 1994; 269: 31334–7
Davisson RL, Kim HS, Krege JH, et al. Complementation of reduced survival, hypotension, and renal abnormalities in angiotensinogen-deficient mice by the human renin and human angiotensinogen genes. J Clin Invest 1997; 99: 1258–64
Sinnayah P, Mckinley MJ, Coghlan JP. Angiotensinogen antisense oligonucleotides and fluid intake. Clin Exp Hyperten 1997; 19: 993–1007
Krege JH, John SW, Langenbach LL, et al. Male-female differences in fertility and blood pressure in ACE-deficient mice. Nature 1995; 375: 146–8
Esther CR, Marino EM, Howard TE, et al. The critical role of tissue angiotensin-converting enzyme as revealed by gene targeting in mice. J Clin Invest 1997; 99: 2375–85
Callahan MF, Li P, Ferrario CM, et al. Salt-sensitive hypertension in (mREN-2)27 transgenic rats. Hypertension 1996; 27: 573–7
Rohmeiss P, Beyer C, Hocher B, et al. Osmotically induced natriuresis and blood pressure response involves angiotensin AT (1) receptors in the subfornial organ. J Hypertens 1995; 13: 1399–1404
Li P, Morris M, Diz DI, et al. Role of paraventricular angiotensin AT1 receptors in salt-sensitive hypertension in mRen-2 transgenic rats. Am J Physiol 1996; 270: R1178–81
Phillips MI. Antisense inhibition and adeno-associated viral vector delivery for reducing hypertension. Hypertension 1997; 29: 177–87
Gyurko R, Tran D, Phillips MI. Time course of inhibition of hypertension by antisense oligoneucleotides targeted to AT(1) angiotensin receptor mRNA in spontaneously hypertensive rats. Am J Hyperten 1997; 10 (5 Part 2) Pt 2: S56–62
Lu D, Raizada MK, Iyer S, et al. Losartan versus gene therapy — chronic control of high blood pressure in spontaneously hypertensive rats. Hypertension 1997; 30: 363–70
Philips MI, Mohuczydominiak D, Coffey M, et al. Prolonged reduction of high blood pressure with an in vivo, nonpathogenic, adeno-associated viral vector delivery of AT(1)-R mRNA antisense. Hypertension 1997; 29: 374–80
Bhoola KD, Figueroa CD, Worthy K. Bioregulation of kinins: kallikreins, kininogens, and kininases. Pharmacol Rev 1992; 44: 1–80
Yang HYT, Erdös EG, Levin Y. A dipeptidyl carboxypeptidase that converts angiotensin I and inactivates bradykinin. Biochim Biophys Acta 1970; 214: 374–6
Margolius HS. Tissue kallikreins and kinins: regulation and roles in hypertensive and diabetic diseases. Ann Rev Pharmacol Toxicol 1989; 29: 343–64
Margolius HS, Geller R, de Jong W, et al. Altered urinary kallikrein excretion in human hypertension. Lancet 1971; II: 1063–5
Zinner SH, Margolius HS, Rosner B, et al. Stability of blood pressure rank and urinary kallikrein concentration in childhood: an eight year follow-up. Circulation 1978; 58: 908–15
Berry TD, Hasstedt SJ, Hunt SC, et al. A gene for high urinary kallikrein may protect against hypertension in Utah kindreds. Hypertension 1989; 17: 242–6
Overlack A, Stumpe KO, Kolloch R, et al. Antihypertensive effect of orally administered glandular kallikrein in essential hypertension. Results of double blind study. Hypertension 1981; 3: 118–21
Wang J, Xiong W, Yang Z, et al. Human tissue kallikrein induces hypotension in transgenic mice. Hypertension 1994; 23: 236–43
Song Q, Chao J, Chao L. High level of circulating human tissue kallikrein induces hypotension in a transgenic mouse model. Clin Exp Hypertens 1996; 18: 975–93
Wang DZ, Chao L, Chao J. Hypotension in transgenic mice overexpressing human bradykinin B2 receptor. Hypertension 1997; 29: 488–93
Wang C, Chao L, Chao J. Direct gene delivery of human tissue kallikrein reduces blood pressure in spontaneously hypertensive rats. J Clin Invest 1995; 95: 1710–6
Xiong W, Chao J, Chao L. Muscle delivery of human kallikrein gene reduces blood pressure in hypertensive rats. Hypertension 1995; 25: 715–9
Jin L, Zhang JJ, Chao L, et al. Gene therapy in hypertension — Adenovirus-mediated kallikrein gene delivery in hypertensive rats. Human Gene Ther 1997; 8(1): 753–61
Yayama K, Wang C, Chao L, et al. Kallikrein gene delivery attenuates hypertension, cardiac hypertrophy and enhances renal function in Goldblatt hypertensive rats. Hypertension 1998; 31: 1104–10
Chao J, Zhang JJ, Lin KF, et al. Human kallikrein gene delivery attenuates hypertension, cardiac hypertrophy, and renal injury in Dahl salt-sensitive rats. Human Gene Ther 1998; 9: 21–31
Chao J, Jin L, Chen LM, et al. Systemic and portal vein delivery of human kallikrein gene reduces blood pressure in hypertensive rats. Human Gene Ther 1996; 7: 901–11
Chao J, Yang ZR, Jin L, et al. Kallikrein gene therapy in newborn and adult hypertensive rats. Can J Physiol Pharmacol 1997; 75: 750–6
Wang C, Chao C, Madeddu P, et al. Central delivery of human tissue kallikrein gene reduces blood pressure in hypertensive rats. Biochem Biophys Res Commun 1998; 244: 449–54
Madeddu P, Parpaglia PP, Glorioso N, et al. Antisense inhibition of the brain kallikrein-kinin system. Hypertension 1996; 28: 980–7
Emanueli C, Chao J, Regoli D, et al. Role of the brain bradykinin B 1-receptor in the central regulation of blood pressure in rats [abstract]. High Blood Pressure Council Meeting, 1997: Sep 16–19; Washington, DC: P68
de Bold AJ. Atrial natriuretic factor: a hormone produced by the heart. Science 1986; 230: 767–70
Conte G, Bellizzi V, Cianciaruso B, et al. Physiological role and diuretic efficacy of atrial natriuretic peptide in health and chronic renal disease. Kidney Int 1997; 51 (Suppl. 59): S28–32
Laragh JH. Atrial natriuretic hormone, the renin-aldosterone axis, and blood pressure-electrolyte homeostasis. N Engl J Med 1985; 313: 1330–40
Brenner BM, Ballermann BJ, Gunning ME, et al. Diverse biological actions of atrial natriuretic peptide. Physiol Rev 1990; 70: 665–99
Cahill PA, Hassid A. ANF-C-receptor-mediated inhibition of aortic smooth muscle cell proliferation and thymidine kinase activity. Am J Physiol 1994; 266: R194–203
Pedram A, Razandi M, Hu RM, et al. Vasoactive peptides modulate vascular endothelial cell growth factor production and endothelial cell proliferation and invasion. J Biol Chem 1997; 272: 17097–103
Steinhelper ME, Cochrane KL, Field LJ. Hypotension in transgenic mice expressing atrial natriuretic factor fusion genes. Hypertension 1990; 16: 301–7
Simon WM, Krege JH, Oliver PM, et al. Genetic decreases in atrial natriuretic peptide and salt-sensitive hypertension. Science 1995; 267: 679–81
Lin KF, Chao J, Chao L. Human atrial natriuretic peptide gene delivery reduces blood pressure in hypertensive rats. Hypertension 1995; 26: 847–53
Lin KF, Chao J, Chao L. Atrial natriuretic peptide gene delivery attenuates hypertension, cardiac hypertrophy and renal injury in salt-sensitive rats. Human Gene Ther 1998; 9: 1429–38
Kitamura K, Kangawa K, Kawamoto M, et al. Adrenomedullin: a novel hypotensive peptide isolated form human pheochromocytoma. Biochem Biophys Res Commun 1993; 192: 553–60
Sakata J, Shimokubo T, Kitamura K, et al. Molecular cloning and biological activities of rat adrenomedullin, a hypotensive peptide. Biochem Biophys Res Commun 1993; 195: 921–7
Sakata J, Shimokubo T, Kitamura K, et al. Distribution and characterization of immunoreactive rat adrenomedullin in tissue and plasma. FEBS Lett 1994; 52: 105–8
Hirata Y, Hayakawa H, Suzuki Y, et al. Mechanisms of adrenomedullin-induced vasodilation in the rat kidney. Hypertension 1995; 25: 790–5
Ishiyama Y, Kitamura K, Ichiki Y, et al. Hemodynamic effects of a novel hypotensive peptide, human adrenomedullin, in rats. Eur J Pharmacol 1993; 241: 271–3
Tsuruda T, Kato J, Kitamura K, et al. Adrenomedullin: a possible autocrine or paracrine inhibitor of hypertrophy of cardiomyocytes. Hypertension 1998; 31: 505–10
Sugo S, Minamino N, Shoji H, et al. Production and secretion of adrenomedullin from vascular smooth muscle cells: augmented production by tumor necrosis factor-α. Biochem Biophys Res Commun 1994; 203: 719–26
Kohno M, Yokokawa K, Kano H, et al. Adrenomedullin is a potent inhibitor of angiotensin II-induced migration of human coronary artery smooth muscle cells. Hypertension 1997; 29: 1309–13
Chao J, Jin L, Lin KF, et al. Adrenomedullin gene delivery reduces blood pressure in spontaneously hypertensive rats. Hypertens Res 1997; 20: 269–77
Palmer RMJ, Ashton DS, Moncada S. Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature 1988; 333: 664–6
Huang PL, Huang Z, Mashimo H, et al. Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature 1995; 377: 239–42
Matsuoka H, Nakata M, Kohno K, et al. Chronic L-arginine administration attenuates cardiac hypertrophy in spontaneously hypertensive rats. Hypertension 1996; 27: 14–8
Arnal JF, Amrani AI, Chatellier G, et al. Cardiac weight in hypertension induced by nitric oxide synthase blockade. Hypertension 1993; 22: 380–7
von der Leyen HE, Gibbons GH, Morishita R, et al. Gene therapy inhibiting neointimal vascular lesion: in. vivo transfer of endothelial cell nitric oxide synthase gene. Proc Natl Acad Sci 1995; 92: 1137–41
Cable DG, O’Brien T, Kullo IJ, et al. Expression and function of a recombinant endothelial nitric oxide synthase gene in porcine coronary arteries. Cardiovas Res 1997; 35: 553–9
Chen AFY, Jiang SW, Crotty TB, et al. Effects of in vivo adenoventitial expression of recombinant endothelial nitric oxide synthase gene in cerebral arteries. Proc Natl Acad Sci 1997; 94: 12568–73
Lin KF, Chao L, Chao J. Prolonged reduction of high blood pressure with human nitric oxide synthase gene delivery. Hypertension 1997; 30: 307–13
Uehara Y, Hirawa N, Kawabata Y, et al. Long-term infusion of kallikrein attenuates renal injury in Dahl salt-sensitive rats. Hypertension 1994; 24: 770–8
Murakami H, Yayama K, Chao L, et al. Human kallikrein gene delivery protects against gentamicin-induced nephrotoxicity in rats. Kidney Int 1998; 53: 1305–13
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Chao, J., Wang, C. & Chao, L. Gene Therapy for Hypertension. BioDrugs 11, 43–53 (1999). https://doi.org/10.2165/00063030-199911010-00005
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DOI: https://doi.org/10.2165/00063030-199911010-00005