Intravenous angiotensinogen antisense in AAV-based vector decreases hypertension

Tang, Xiaoping; Mohuczy, Dagmara; Zhang, Y. Clare; Kimura, Birgitta; Galli, Sara M.; Phillips, M. Ian

doi:10.1152/ajpheart.1999.277.6.h2392

Cited by 22 publications

(16 citation statements)

References 36 publications

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“…Because the brain renin-angiotensin system is considered important for cardiovascular regulation and it has been reported that SHR present an augmented central angiotensin II (Ang II) synthesis and Ang II receptor number, and antisense treatments against angiotensinogen, angiotensin converting enzyme, or the angiotensin type I receptor (AT 1 ) normalizes blood pressure in these animals, [12][13][14][15][16] we also measured diencephalic Ang II content in our experiments. We found that TRH antisense treatment decreases the Ang II diencephalic content to values comparable to those of the WKY control rats To summarize, these results pointed out that (1) the central TRH system participates in the development or maintenance of hypertension in this rat model, and (2) the TRH cardiovascular effects are independent of its classic endocrine function in the hypothalamus-pituitary axis and seems to involve the encephalic renin-angiotensin system.…”

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confidence: 99%

Antisense Inhibition of Thyrotropin-Releasing Hormone Reduces Arterial Blood Pressure in Spontaneously Hypertensive Rats

et al. 2001

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Abstract-Thyrotropin-releasing hormone (TRH) plays an important role in central cardiovascular regulation. Recently, we described that the TRH precursor gene overexpression induces hypertension in the normal rat. In addition, we published that spontaneously hypertensive rats (SHR) have central extrahypothalamic TRH hyperactivity with increased TRH synthesis and release and an elevated TRH receptor number. In the present study, we report that intracerebroventricular antisense (AS) treatment with a phosphorothioate oligonucleotide against the TRH precursor gene significantly diminished up to 72 hours and in a dose-dependent manner the increased diencephalic TRH content, whereas normalized systolic blood pressure (SABP) was present in the SHR compared with Wistar-Kyoto (WKY) rats. Although basal thyrotropin was higher in SHR compared with WKY rats and this difference disappeared after antisense treatment, no differences were observed in plasma T4 or T3 between strains with or without AS treatment, indicating that the effect of the AS on SABP was independent of the thyroid status. Because the encephalic renin-angiotensin system seems to be crucial in the development and/or maintenance of hypertension in SHR, we investigated the effect of antisense inhibition of TRH on that system and found that TRH antisense treatment significantly diminished the elevated diencephalic angiotensin II (Ang II) content in the SHR without any effect in control animals, suggesting that the Ang II system is involved in the TRH cardiovascular effects. To summarize, the central TRH system seems to be involved in the etiopathogenesis of hypertension in this model of essential hypertension. Key Words: angiotensin II Ⅲ antisense Ⅲ blood pressure Ⅲ hypertension Ⅲ SHR Ⅲ thyroid hormones Ⅲ TRH Ⅲ TSH I n addition to its endocrine function, thyrotropin-releasing hormone (TRH; pyro-Glu-His-Pro-amide) also serves as a neurotransmitter in the central nervous system. 1 TRH immunoreactivity is widely distributed throughout the central nervous system, including the brain and spinal cord. 2 Although the lack of antagonists to the TRH receptor has made difficult to determine the physiological role for the extrahypothalamic TRH system, its presence in brain nuclei involved in cardiovascular regulation, such as the periventricular region and the preoptic area, suggests that this tripeptide may modulate the cardiovascular function. 3 In fact, many groups have described that brain microinjections of TRH produce dose-dependent pressor effects. 4 Recently, we have reported that the overexpression of the TRH precursor in the third ventricle of the central nervous system of normal rats induces a long-lasting elevation of arterial blood pressure along with an increase in the diencephalic TRH content in a dose-dependent manner. These effects were specifically reversed by an antisense treatment, indicating that the extrahypothalamic TRH system effectively participates in cardiovascular regulation in the rat. 5 Spontaneously hypertensive rats (SHR) have been extensive...

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confidence: 99%

Antisense Inhibition of Thyrotropin-Releasing Hormone Reduces Arterial Blood Pressure in Spontaneously Hypertensive Rats

et al. 2001

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“…30 AGT-AS expression was positive in heart and lung at 3 days and at 7 days. Expression in the kidney was weak or absent.…”

Section: Delivery By Plasmidsmentioning

confidence: 92%

“…40,30 The results showed that single intracardiac injection of rAAV-AT 1 R-AS effectively reduced blood pressure by 30 mm Hg for at least 5 weeks compared with controls.…”

Section: Delivery By Recombinant Aav Vectormentioning

confidence: 99%

“…This is illustrated with the adeno-associated vector for AGT antisense cDNA. 30 A plasmid containing AAV terminal repeats was prepared with a cassette, consisting of a cytomegalovirus (CMV) promoter, the rat AGT cDNA based on the sequence by Lynch et al 43 The cDNA is oriented in the antisense direction. In addition, the cassette contains an internal ribosome entry site and, as a marker, the green fluorescent protein gene.…”

Section: Delivery By Plasmidsmentioning

confidence: 99%

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Gene Therapy for Hypertension

Phillips

2001

Hypertension

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Abstract-Despite several drugs for the treatment of hypertension, there are many patients with poorly controlled high blood pressure. This is partly because all of the available drugs are short-lasting (Յ24 hours), have side effects, and are not highly specific. Gene therapy offers a possibility of producing longer-lasting effects with precise specificity based on the genetic design. Preclinical studies on gene therapy for hypertension have taken 2 approaches. Chao et al have performed extensive studies on gene transfer to increase vasodilator proteins. They have transferred kallikrein, atrial natriuretic peptide, adrenomedullin, and endothelin NO synthase into different rat models. Their results show that blood pressure can be lowered for 3 to 12 weeks with the expression of these genes. The antisense approach, which we began by targeting angiotensinogen and the angiotensin type 1 (AT 1 ) receptor, has now been tested independently by several different groups in multiple models of hypertension. Other genes targeted include the ␤ 1 -adrenoceptor, thyrotropinreleasing hormone, angiotensin gene-activating elements, carboxypeptidase Y, c-fos, and CYP4A1. There have been 2 methods of delivering antisense: one is by oligodeoxynucleotides, and the other is with full-length DNA in viral vectors.All the studies show a decrease in blood pressure lasting several days to weeks or months. Oligos are safe and nontoxic and could be delivered orally or eventually by skin patches. Systemic delivery of recombinant adeno-associated virus with DNA antisense to AT 1 receptors in adult rodents decreases hypertension for up to 6 months. We conclude that there is sufficient preclinical data to give serious consideration to phase I trials for testing some of the antisense oligodeoxynucleotides, although testing the viral vectors needs much more work.

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“…Liposome complexed or naked AAV-plasmid DNA have been administered intravenously in rodent models, resulting in transgene expression in multiple organs. 59,60 However, additional experiments are needed to confirm the reproducibility of this strategy.…”

Section: Development Of Raav Vectors From Different Serotypesmentioning

confidence: 99%