scholarly journals CRISPR/Cas9 Mediated Deletion of the Angiotensinogen Gene Reduces Hypertension

Hypertension ◽  
2021 ◽  
Author(s):  
Hualing Sun ◽  
Conrad P. Hodgkinson ◽  
Richard E. Pratt ◽  
Victor J. Dzau
Keyword(s):  
Blood Pressure ◽  
Spontaneously Hypertensive Rat ◽  
Renin Angiotensin System ◽  
Pressure Control ◽  
Spontaneously Hypertensive ◽  
Sustained Reduction ◽  
Short Palindromic Repeat ◽  
Spontaneously Hypertensive Rat Model ◽  
Agt Gene

Hypertension is a major contributor to the global burden of disease. Unfortunately, hypertension is controlled in less than one-fifth of patients worldwide due to either failure to treat or lack of compliance to medication. An ideal therapy would be administered one time only and yield lifelong blood pressure control. We investigated our hypothesis that CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat–associated 9)-mediated disruption of a key gene in the renin-angiotensin system, AGT (angiotensinogen), specifically in the liver, would result in sustained and possibly lifelong reduction in blood pressure. We demonstrated in vitro that the CRISPR/Cas9 system led to a significant reduction in AGT expression in hepatocytes. Delivery of the CRISPR/Cas9 system into the liver via the hepatocyte-targeting adeno-associated virus 8 reduced both AGT expression (40% decrease) and circulating AGT levels (30% decrease). In the SHR (spontaneously hypertensive rat) model of hypertension, CRISPR/Cas9-mediated loss of AGT expression reduced blood pressure in adult animals with established hypertension and prevented the spontaneous development of hypertension in young SHR. Moreover, reductions in blood pressure were prolonged and sustained up to 1 year of follow-up. In addition, the partial disruption of the hepatic AGT gene was sufficient to control hypertension but did not affect the homeostatic response to cardiovascular stress such as sodium depletion and furosemide. In summary, we have demonstrated that targeting the CRISPR/Cas9 system to hepatic AGT results in sustained reduction of blood pressure and is a potential therapy to achieve sustained and possibly lifelong control of human hypertension.

Aberrant baroreceptor mechanotransduction in adult Dahl rats on low-salt diet

1989 ◽  
Vol 256 (2) ◽  
pp. H446-H454 ◽  
Author(s):  
M. C. Andresen ◽  
S. K. Rudis ◽  
D. E. Bee
Keyword(s):  
Blood Pressure ◽  
Aortic Wall ◽  
Spontaneously Hypertensive Rat ◽  
Cumulative Distribution ◽  
Salt Diet ◽  
Spontaneously Hypertensive ◽  
Low Salt ◽  
Blood Pressures ◽  
Spontaneously Hypertensive Rat Model

Single fiber, regularly discharging baroreceptors (n = 118) from adult Dahl salt-sensitive (DS) and salt-resistant (DR) rats on a low-salt diet were studied using an in vitro aortic arch-aortic nerve preparation. Pressure thresholds (Pth) and suprathreshold pressure sensitivities (Sth) were determined from responses to slow ramps of pressure. Pressure-diameter relationships measured in each rat were used to transform Pth and Sth values to their mechanical equivalents in terms of aortic wall strain. DS and DR ages were not different (approximately 50 wk). Despite the low-salt diet, DS tail systolic blood pressures were significantly higher than DR by approximately 25 mmHg. Pth averaged 84 mmHg in DR and 97 mmHg in DS. Sth values were similar in DR and DS (average 1.44 and 1.39 spikes.s-1.mmHg-1 in DR and DS, respectively). Increased variance of baroreceptor properties of DS over DR was a prominent finding and necessitated use of nonparametric statistics. The cumulative distribution of Pth values of DS was significantly different from DR, but Sth values were similar. Thus baroreceptor pressure set points are altered in adult DS, but pressure sensitivity per se is not. The differences in pressure parameters were not eliminated by conversion to their mechanical equivalents. Correlation analysis found only weak relationships between Pth and blood pressure for DS and DR (r less than 0.40). Thus in contrast to previous studies in the spontaneously hypertensive rat model, baroreceptors in adult DS on low salt are characterized by elevated variability and a weaker than expected correlation to the prevailing blood pressure in the animal.(ABSTRACT TRUNCATED AT 250 WORDS)

Antihypertensive effect of mechanism-based inhibition of renal arachidonic acid ω-hydroxylase activity

2002 ◽  
Vol 283 (3) ◽  
pp. R710-R720 ◽  
Author(s):  
Fengyun Xu ◽  
Wesley O. Straub ◽  
Winnie Pak ◽  
Ping Su ◽  
Kristopher G. Maier ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Spontaneously Hypertensive Rat ◽  
Spontaneously Hypertensive ◽  
Arterial Blood ◽  
Vasoconstrictor Response ◽  
Potent Vasoconstrictor ◽  
Acetylenic Fatty Acid ◽  
Regulation Of Blood Pressure

The cytochrome P-450 eicosanoid 20-hydroxyeicosatetraenoic acid (20-HETE) is a potent vasoconstrictor that is implicated in the regulation of blood pressure. The identification of selective inhibitors of renal 20-HETE formation for use in vivo would facilitate studies to determine the systemic effects of this eicosanoid. We characterized the acetylenic fatty acid sodium 10-undecynyl sulfate (10-SUYS) as a potent and selective mechanism-based inhibitor of renal 20-HETE formation. A single dose of 10-SUYS caused an acute reduction in mean arterial blood pressure in 8-wk-old spontaneously hypertensive rats. The decrease in mean arterial pressure was maximal 6 h after 10-SUYS treatment (17.9 ± 3.2 mmHg; P < 0.05), and blood pressure returned to baseline levels within 24 h after treatment. Treatment with 10-SUYS was associated with a decrease in urinary 20-HETE formation in vivo and attenuation of the vasoconstrictor response of renal interlobar arteries to ANG II in vitro. These results provide further evidence that 20-HETE plays an important role in the regulation of blood pressure in the spontaneously hypertensive rat.

Cell Membrane Microviscosity and Ca2+-Mg2+-ATPase Activity do Not Contribute to Hypertension in the Spontaneously Hypertensive Rat Model

1993 ◽  
Vol 85 (5) ◽  
pp. 585-591 ◽  
Author(s):  
Robert I Norman ◽  
Navtej Achall
Keyword(s):  
Blood Pressure ◽  
Atpase Activity ◽  
Spontaneously Hypertensive Rats ◽  
Spontaneously Hypertensive Rat ◽  
Hypertensive Rats ◽  
Membrane Microviscosity ◽  
Spontaneously Hypertensive ◽  
Blood Pressures ◽  
Wistar Kyoto ◽  
Spontaneously Hypertensive Rat Model

1. The relationships between systolic blood pressure and altered erythrocyte Ca2+-Mg2+-ATPase activity and membrane microviscosity were assessed in membranes prepared from 20-week-old female Wistar-Kyoto normotensive and spontaneously hypertensive rats obtained from two different sources (Charles River and Harlan OLAC) and a second filial (F2) generation derived from a cross between Wistar-Kyoto rats and spontaneously hypertensive rats from one source (Charles River). 2. Spontaneously hypertensive rats from both sources had systolic blood pressures significantly higher than those of Wistar-Kyoto animals (P <0.05; 151 + 4 and 110 + 3 mmHg, Charles River; 155 + 4 and 122 + 4 mmHg, Harlan OLAC). The systolic blood pressures for the F2 rat population ranged between 73 and 168 mmHg. 3. Ca2+-Mg2+-ATPase activity was measured as ATP-dependent 45Ca2+ uptake into inside-out vesicles and microviscosity assessed by the measurement of polarization anisotropy of membrane incorporated fluorescent probes including 1,6-diphenyl-1,3,5-hexatriene, trimethylamino-1,6-diphenyl-1,3,5-hexatriene and a series of anthroyloxy fatty acids. 4. Contrary to previous studies, no relationship between adult systolic blood pressure and erythrocyte Ca2+-Mg2+-ATPase activity or general or localized membrane microviscosity was indicated by the comparison of spontaneously hypertensive and Wistar-Kyoto animals or in the analysis of the F2 rat population. 5. These results suggest that Ca2+-Mg2+-ATPase activity and membrane microviscosity are causally unrelated to hypertension in these animals. On the assumption that biophysical properties of the erythrocyte membrane reflect those of smooth muscle, our results suggest that membrane alteration does not play a significant role in the pathogenesis of hypertension in the spontaneously hypertensive rat model.

Role of Vasopressin in Blood Pressure Control of Spontaneously Hypertensive Rats

1978 ◽  
Vol 55 (s4) ◽  
pp. 247s-250s ◽  
Author(s):  
Jan Möhring ◽  
Jacqueline Kintz ◽  
Josiane Schoun
Keyword(s):  
Blood Pressure ◽  
Blood Pressure Control ◽  
Spontaneously Hypertensive Rats ◽  
Salt Intake ◽  
Renin Angiotensin System ◽  
Pressure Control ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
High Salt Intake

1. The role of arginine—vasopressin (AVP) and of angiotensin in blood pressure control of spontaneously hypertensive rats (SH rats, stroke-prone strain) was studied. 2. In SH rats, which drank water or 1% NaCl, plasma AVP concentrations were elevated during the benign course of hypertension and increased further when the animals entered the malignant phase. Blood pressure correlated significantly with plasma AVP concentrations in SH rats on water, but not in SH rats on saline. 3. The injection of a specific AVP antiserum lowered blood pressure significantly in SH rats on water and in SH rats on saline. 4. When the correlation between blood pressure and plasma AVP of SH rats on water was compared with the respective correlation obtained during infusion of AVP into normotensive rats, a marked shift to the left became apparent, the factor of displacement amounting to more than 1000. 5. Saralasin did not affect blood pressure of SH rats on water, except for two rats with malignant hypertension. However, in SH rats on saline, saralasin lowered blood pressure significantly. 6. It is concluded that in SH rats AVP plays an important vasopressor role in blood pressure control and that sensitization to the vasopressor effect of AVP occurs in these animals. The renin—angiotensin system is significantly involved in blood pressure control of SH rats only when they are subjected to high salt intake.

scholarly journals Chronic NO Restriction in Hypertensive Rats Increases Abdominal but Not Thoracic Aortic Intrinsic Stiffness via an Augmentation in Profibrotic Materials

2019 ◽  
Vol 2019 ◽  
pp. 1-11
Author(s):  
George Lindesay ◽  
Yvonnick Bézie ◽  
Christophe Ragonnet ◽  
Véronique Duchatelle ◽  
Marc Isabelle ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Spontaneously Hypertensive Rat ◽  
Dynamic Properties ◽  
Stiffness Index ◽  
Operating Pressure ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Wistar Kyoto ◽  
Spontaneously Hypertensive Rat Model

The spontaneously hypertensive rat model with reduced NO synthesis (SHRLN) shares features with aging and hypertension in humans, among other a severe aortic stiffening. The present in vivo study aimed to compare thoracic (TA) and abdominal (AA) aortic stiffness in the SHRLN (treated 5 weeks with L-NAME), SHR, and normotensive Wistar Kyoto (WKY). Dynamic properties of TA and AA were measured in the same rats, using echotracking recording of aortic diameter coupled with blood pressure (BP). Measurements were performed first at operating BP and then after BP reduction in hypertensive rats, thus in isobaric conditions. Histological staining and immunohistochemistry were used for structural analysis at both sites. At operating pressure, BP and pulse pressure (PP) were higher in SHRLN compared with SHR. Stiffness index was also increased and distensibility decreased in both TA and AA in SHRLN. At WKY-matched blood pressure, isobaric AA parameters remained specifically altered in SHRLN, whereas TA recovered to values identical to WKYs. Collagen, fibronectin, α5-selectin, and FAK were increased in SHRLN compared with SHR or WKY. Nevertheless, only the strong accumulations of fibronectin and collagen at the AA site in SHRLN were associated with intrinsic stiffening. In conclusion, we confirm that NO restriction associated with hypertension induces a severe pathological phenotype and shows that L-NAME induced stiffening is more pronounced in AA than in TA as a result of greater fibrosis.

Abstract 15555: Potential Cure for Hypertension? The Effect of Crispr Genome Editing

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Hualing Sun ◽  
Conrad Hodgkinson ◽  
Richard E Pratt ◽  
Victor J Dzau
Keyword(s):  
Blood Pressure ◽  
Systolic Blood Pressure ◽  
Pressure Control ◽  
Systemic Delivery ◽  
Protein Levels ◽  
Cardiovascular Stress ◽  
Medical Compliance ◽  
Agt Gene

Hypertension is recognized as one of the largest contributors to the global burden of disease. Unfortunately, for the majority of patients, hypertension is poorly controlled due, in part, to poor medical compliance resulting from the need to take one or more drugs, often several times daily. An ideal therapy would be administered a single time but yield long-term blood pressure control. Under the appropriate condition, we hypothesize that this modality could potentially lead to a cure for hypertension. In this study, we investigated whether that sustained, and possibly life-long, reductions in blood pressure could be achieved via Crispr-Cas9 mediated disruption of a key gene in the RAAS, Angiotensinogen (AGT). In vitro, we demonstrated that expression of Crispr-Cas9 system in the BRL 3A rat liver cell line led to a significant reduction in AGT protein levels (75% reduction, N=3, P<0.01). Delivery of the Crispr-Cas9 system into the liver via systemic delivery of the hepatocyte-targeting AAV8 reduced both AGT mRNA (70% reduction, N=5, P<0.01) and circulating AGT protein (50% reduction, N=5, P<0.01) and Ang II levels (33% reduction, n=5, P<0.01). In the SHR model of hypertension, Crispr-Cas9 mediated loss of AGT expression reduced systolic blood pressure in adult animals with established hypertension (30-35mmHg decrease in both females and males, N=12, P<0.001). Importantly, AGT gene disruption also prevented the spontaneous development of hypertension in young pre-hypertensive SHR (SHR control: 55-60mmHg increase in systolic blood pressure both female and male SHR; SHR plus Crispr-Cas9: 30-33 mmHg increase. N=12. P<0.001). Importantly, in all the models studied, reductions in blood pressure were sustained for at least 4 months. Importantly, the partial disruption of the hepatic AGT gene was sufficient to control hypertension but did not block the renin-angiotensin response to cardiovascular stress such as sodium depletion. In summary, we have demonstrated that targeting the Crispr-Cas9 system to RAAS reduces blood pressure and may be a potential therapy to achieve safe and sustained, possibly life-long, control of hypertension and this approach maybe a cure for hypertension.

scholarly journals Sex differences in hypertension: lessons from spontaneously hypertensive rats (SHR)

2021 ◽  
Vol 135 (15) ◽  
pp. 1791-1804
Author(s):  
Ahmed A. Elmarakby ◽  
Jennifer C. Sullivan
Keyword(s):  
Blood Pressure ◽  
Sex Differences ◽  
Blood Pressure Control ◽  
Spontaneously Hypertensive Rats ◽  
Experimental Studies ◽  
Renin Angiotensin System ◽  
Pressure Control ◽  
Hypertensive Rats ◽  
Angiotensin System ◽  
Spontaneously Hypertensive

Abstract Although numerous clinical and experimental studies have clearly identified a sexual dimorphism in blood pressure control, the mechanism(s) underlying gender differences in blood pressure remain unclear. Over the past two decades, numerous laboratories have utilized the spontaneously hypertensive rats (SHR) as an experimental model of essential hypertension to increase our understanding of the mechanisms regulating blood pressure in males and females. Previous work by our group and others have implicated that differential regulation of adrenergic receptors, the renin–angiotensin system, oxidative stress, nitric oxide bioavailability and immune cells contribute to sex differences in blood pressure control in SHR. The purpose of this review is to summarize previous findings to date regarding the mechanisms of blood pressure control in male versus female SHR.

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