Hypertension is a complex pathological state that is manifested as chronic blood pressure. It affects all vital organs, and is a major risk for many cardiovascular diseases. Overwhelming evidence has established that an altered renin-angiotensin system (RAS) plays a key role in the development and establishment of hypertension. Thus, traditional pharmacological agents that influence the RAS are effective antihypertensive therapy. In spite of its success, the traditional therapy is not a cure of hypertension and suffers from many side effects and compliance issues. As a result, the investigators set out to investigate the possibility of genetic targeting of the RAS as a means to control hypertension on a long-term basis. Their studies have established that a single dose of a retroviral vector containing angiotensin II type I receptors antisense (AT1R-AS) or angiotensin-converting enzyme antisense (ACE-AS) prevents hypertension for life in the spontaneously hypertensive rat (SHR). These observations led them to conclude that the antisense therapy (AS) is conceptually sound, technically feasible, and may hold promise for cure of hypertension. The objective during this grant period is to test an overall hypothesis that AS targeting to regulate the expression of the RAS would prevent the development of hypertension on a permanent basis as a result of genomic integration of AT1R-AS or ACE-AS. If successful, a regulatable system of the AS, and thus antihypertensive actions, could be controlled on demand.
The aims of the study are: 1) investigate the mechanism of a long-term protection against hypertension by the AT1R-AS gene therapy; 2) investigate involvement of central angiotensin in antihypertensive actions of AT1R-AS gene therapy; 3) investigate the role of tissue RAS in hypertension, and 4) establish long-term reversal of hypertension by the use of a novel viral vector system. State-of-the-art techniques of gene transfer, viral vectors, and molecular biology will be used to accomplish these aims. The investigators believe that this research proposal is low risk in nature and will have high impact in the development of strategies for long-term control of hypertension. The outcome of this research has a potential to be immediately adapted for the treatment of human hypertension and other cardiovascular diseases.
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