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Angiotensin I-converting enzyme antisense gene therapy causes permanent antihypertensive effects in the SHR
H Wang1, P Y Reaves, M L Gardon
1Department of Physiology, College of Medicine, University of Florida, and the University of Florida Brain Institute, Gainesville, FL 32610-0274, USA.
Insights
Gene therapy targeting angiotensin-converting enzyme (ACE) mRNA prevented hypertension in spontaneously hypertensive rats and transmitted this normotensive trait to their offspring. This approach offers a potential new strategy for managing hypertension.
Area of Science:
- Cardiovascular Research
- Gene Therapy
- Hypertension Pathophysiology
Background:
- The renin-angiotensin system is crucial for blood pressure regulation; its hyperactivity contributes to hypertension.
- Traditional therapies for hypertension have limitations.
- Antisense gene delivery offers a novel strategy to overcome these limitations.
Purpose of the Study:
- To investigate if targeting angiotensin I-converting enzyme (ACE) mRNA with antisense strategy prevents hypertension development in spontaneously hypertensive rats (SHR).
- To determine if the antihypertensive effect is heritable to offspring from treated SHR parents.
Main Methods:
- Administration of a retroviral vector containing ACE antisense (LNSV-ACE-AS) to SHR.
- Assessment of blood pressure, cardiac hypertrophy, and renovascular function in treated SHR and their offspring.
- Genomic analysis to confirm ACE-AS integration and transmission.
Main Results:
- LNSV-ACE-AS treatment significantly reduced blood pressure in SHR, preventing cardiac and renovascular abnormalities.
- Offspring (F1 generation) of treated SHR exhibited lower blood pressure, reduced cardiac hypertrophy, and normalized renal function.
- Endothelial dysfunction in renal arterioles was prevented in both treated parents and offspring.
- ACE-AS was integrated into the SHR genome and transmitted to offspring.
Conclusions:
- Antisense targeting of ACE mRNA via retroviral vector delivery can prevent hypertension in SHR.
- The normotensive phenotype induced by ACE-AS gene therapy can be transmitted to offspring.
- This gene therapy approach holds promise for heritable hypertension management.
Abstract:
The renin-angiotensin system plays a critical role in the control of blood pressure (BP), and its hyperactivity is associated with the development and maintenance of hypertension. Although traditional pharmacological therapies targeted toward the inhibition of the renin-angiotensin system are effective in the control of this disease, they pose significant limitations. We used an antisense gene delivery strategy to circumvent these limitations and established that a single intracardiac administration of angiotensin type 1 receptor antisense (AT(1)R-AS) causes permanent prevention of hypertension in the spontaneously hypertensive rat (SHR), an animal model of primary human hypertension. Our objectives in this study were 2-fold: to determine (1) whether the targeting of angiotensin I-converting enzyme (ACE) mRNA by a similar antisense strategy would prevent the SHR from developing hypertension and (2) whether the antihypertensive phenotype is transmitted to the offspring from the antisense-treated parents. Administration of a retroviral vector containing ACE antisense (LNSV-ACE-AS) caused a modest yet significant attenuation of high BP ( approximately 15+/-2 mm Hg) exclusively in the SHR. This was associated with a complete prevention of cardiac and renovascular pathophysiological alterations that are characteristic of hypertension. Like their parents, the F(1) generation offspring of the LNSV-ACE-AS-treated SHR expressed lower BP, decreased cardiac hypertrophy, and normalization of renal arterial excitation-coupling compared with offspring derived from the LNSV-ACE-tS (truncated sense)-treated SHR. In addition, the endothelial dysfunction commonly observed in the SHR renal arterioles was significantly prevented in both parents and offspring of the LNSV-ACE-AS-treated SHR. Polymerase chain reaction followed by Southern analysis revealed that the ACE-AS was integrated into the SHR genome and transmitted to the offspring. These observations suggest that transmission of ACE-AS by retroviral vector may be responsible for the transference of normotensive phenotypes in the SHR offspring.