Intravenous Injection With Antisense Oligodeoxynucleotides Against Angiotensinogen Decreases Blood Pressure in Spontaneously Hypertensive Rats

Makino, Naoki; Shinoda, Masahiro; Ohtsuka, Shoji; Sawada, Shojiro

doi:10.1161/01.hyp.31.5.1166

Cited by 43 publications

(23 citation statements)

References 26 publications

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“…When given iv the AGT-AS-ODN would reduce blood pressure significantly when delivered with a liposome. These studies have been confirmed by other studies independently, showing that AGT-AS-ODN reduces blood pressure for up to 7 days with a single systemic dose (6). A similar story is true for the effects of AT 1 -AS-ODN.…”

Section: Antisense Oligonucleotidessupporting

confidence: 73%

Somatic gene therapy for hypertension

2000

Braz J Med Biol Res

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Gene therapy for hypertension is needed for the next generation of antihypertensive drugs. Current drugs, although effective, have poor compliance, are expensive and short-lasting (hours or one day). Gene therapy offers a way to produce long-lasting antihypertensive effects (weeks, months or years). We are currently using two strategies: a) antisense oligodeoxynucleotides (AS-ODN) and b) antisense DNA delivered in viral vectors to inhibit genes associated with vasoconstrictive properties. It is not necessary to know all the genes involved in hypertension, since many years of experience with drugs show which genes need to be controlled. AS-ODN are short, single-stranded DNA that can be injected in naked form or in liposomes. AS-ODN, targeted to angiotensin type 1 receptors (AT 1 -R), angiotensinogen (AGT), angiotensin converting enzyme, and ß1-adrenergic receptors effectively reduce hypertension in rat models (SHR, 2K-1C) and coldinduced hypertension. A single dose is effective up to one month when delivered with liposomes. No side effects or toxic effects have been detected, and repeated injections can be given. For the vector, adenoassociated virus (AAV) is used with a construct to include a CMV promoter, antisense DNA to AGT or AT 1 -R and a reporter gene. Results in SHR demonstrate reduction and slowing of development of hypertension, with a single dose administration. Left ventricular hypertrophy is also reduced by AAV-AGT-AS treatment. Double transgenic mice (human renin plus human AGT) with high angiotensin II causing high blood pressure, treated with AAV-AT 1 -R-AS, show a normalization of blood pressure for over six months with a single injection of vector. We conclude that ODNs will probably be developed first because they can be treated like drugs for the treatment of hypertension with long-term effects. Viral vector delivery needs more engineering to be certain of its safety, but one day may be used for a very prolonged control of blood pressure.

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Section: Antisense Oligonucleotidessupporting

confidence: 73%

Somatic gene therapy for hypertension

2000

Braz J Med Biol Res

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“…Intravenous injection of antisense oligonucleotides into spontaneously hypertensive rats resulted in reduction in plasma angiotensinogen, angiotensin II, and blood pressure. 131 Antisense oligonucleotides to AGT injected into the brain of 2-kidney, 1 clip rats also reduced blood pressure substantially. 132 Mice overexpressing AGT only in the brain have elevated blood pressure.…”

Section: Autosomal Recessivementioning

confidence: 98%

Genetics of hypertension

Hopkins

Hunt

2003

Genetics in Medicine

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Hypertension is the most prevalent cardiovascular disorder. In the 1999 to 2000 NHANES survey, the prevalence of hypertension progressively increased from 7.2% in those aged 18 to 39 to 30.1% in 40 to 59 year olds and 65.4% in those 60 and older. 1 Risk of both coronary atherosclerosis and stroke increase exponentially as blood pressure rises (see Fig. 1). 2 Although the relative risk for stroke increases more rapidly than coronary disease, at any pressure, the absolute risk for coronary disease is considerably greater than for stroke. An insight into this finding comes from autopsy studies that show that the carotid and intracerebral vascular beds are relatively protected from atherosclerosis as compared to the coronary circulation, particularly at lower blood pressures (see Fig. 2). 3,4 Probably the major means whereby hypertension accelerates atherosclerosis is through pressure-driven convection of LDL and other atherogenic particles into the arterial intima. 5-8 Indeed, without at least arterial pressures, atherosclerosis does not exist in the vascular tree 9 even in patients with homozygous familial hypercholesterolemia. 10,11 Increased turbulence (a rare occurrence in the human circulatory system) does not increase atherosclerosis. Rather, higher sheer stress is a strong stimulus for release of nitric oxide that locally decreases risk of atherosclerosis. Focal areas of low sheer stress are at inherently increased risk of atherosclerotic disease (such as the coronary arteries where flow stops during each systole). 12 Interestingly, in most studies, stroke risk has been affected little by serum total cholesterol, 13,14 although some recent studies identify clear associated risk. 15 At least some association with all standard cardiovascular risk factors should be expected, not only because thromboembolic stroke may be caused by carotid tree atherosclerosis, but because aortic plaques have been strongly implicated as an embolic source for ischemic stroke. 16 -18 Hypertension is not just a risk factor for atherosclerosis. High blood pressure can have direct adverse effects on arteries, arterioles, and the heart, resulting in potentially severe consequences beyond the more common manifestations of myocardial infarction and atherothrombotic stroke. Even modestly elevated blood pressure is a major risk factor for congestive heart failure. 19,20 Hypertension is a major contributor to left ventricular hypertrophy, a major risk factor for sudden death independent of other risk factors. 21,22 Hypertension can lead progressively to arterial and arteriolar hypertrophy, arteriosclerosis and arteriolosclerosis, and with very high pressures to fibrinoid change and fibrinoid necrosis in arterioles. These latter changes can result in lumen compromise of arterioles resulting in lacunar stroke, Charcot-Bouchard aneurysms, glomerulosclerosis and nephrosclerosis, and ultimately malignant hypertension in the kidney and retinal ischemia and blindness. Risk of intracerebral hemorrhage is increased 33-fold at stage 3 or higher pre...

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“…24 Control ODN of either sense or scrambled sequences of the same length do not decrease BP. The hypertensive effect of AS treatment can be maintained with repeated administration.…”

Section: Phillips January 1999mentioning

confidence: 98%

“…Effective AS ODN have been targeted to mRNA for renin, angiotensinogen, ACE, and AT 1 -R. They have been tested in 3 different models of hypertension, including the genetic model (SHR), [21][22][23][24] a surgical model (2-kidney, 1 clip hypertension [2K1C]), 25 and an environmental stress model (coldinduced hypertension) 26 (Table 1). In every case in which we have tested the selected AS oligomers, there have been consistent biological signs of gene knockdown.…”

Section: The Antisense Oligonucleotide Approachmentioning

confidence: 99%

“…Beneficial effects on the heart and kidneys still need to be tested. The naked AS oligonucleotide is effective, but cationic liposome carriers 22,23 or asialoglycoprotein 24 increases the effectiveness of the AS injected intravenously. The oligonucleotides we used do not appear to be toxic even after repeated injections over months.…”

Section: Phillips January 1999mentioning

confidence: 99%

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